Heteroaromatic glucokinase activators

ABSTRACT

The present invention describes 2,3-di-substituted N-heteroaromatic propionamides, wherein the substitution at the 3-position is an optionally substituted phenyl ring and the substitution at the 2-position is an alkyl or cycloalkyl group; pharmaceutical compositions comprising the same; and, methods of using the same. The propionamides are glucokinase activators which increase insulin secretion for the treatment of type II diabetes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/791,200, filed May 21, 2007, which is a 35 U.S.C. §371 national stageapplication of International Patent Application PCT/EP2005/056473(published as WO 2006/058923 A1), filed Dec. 5, 2005, which claimedpriority of Danish Patent Application PA 2004 01888, filed Dec. 3, 2004.

FIELD OF THE INVENTION

The present invention relates to 2,3-di-substituted N-heteroaromaticpropionamides, pharmaceutical compositions comprising the same, andmethods of using the same. The propionamides are useful as glucokinaseactivators which increase insulin secretion in the treatment of type IIdiabetes.

BACKGROUND OF THE INVENTION

Glucokinase (GK) is one of four hexokinases that are found in mammals[Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press,New York, N.Y., pages 1-48, 1973]. The hexokinases catalyze the firststep in the metabolism of glucose, i.e., the conversion of glucose toglucose-6-phosphate. Glucokinase has a limited cellular distribution,being found principally in pancreatic β-cells and liver parenchymalcells. In addition, GK is a rate-controlling enzyme for glucosemetabolism in these two cell types that are known to play critical rolesin whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., andRuderman, N. B. in Joslin's Diabetes (C. R. Khan and G. C. Wier, eds.),Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. Theconcentration of glucose at which GK demonstrates half-maximal activityis approximately 8 mM. The other three hexokinases are saturated withglucose at much lower concentrations (<1 mM). Therefore, the flux ofglucose through the GK pathway rises as the concentration of glucose inthe blood increases from fasting (5 mM) to postprandial (≈10-15 mM)levels following a carbohydrate-containing meal [Printz, R. G.,Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R.E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc.,Palo Alto, Calif., pages 463-496, 1993]. These findings contributed overa decade ago to the hypothesis that GK functions as a glucose sensor inβ-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer.J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenicanimals have confirmed that GK does indeed play a critical role inwhole-body glucose homeostasis. Animals that do not express GK diewithin days of birth with severe diabetes while animals overexpressingGK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. etal., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEBJ., 10, 1213-1218, 1996). An increase in glucose exposure is coupledthrough GK in β-cells to increased insulin secretion and in hepatocytesto increased glycogen deposition and perhaps decreased glucoseproduction.

The finding that type II maturity-onset diabetes of the young (MODY-2)is caused by loss of function mutations in the GK gene suggests that GKalso functions as a glucose sensor in humans (Liang, Y., Kesavan, P.,Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidencesupporting an important role for GK in the regulation of glucosemetabolism in humans was provided by the identification of patients thatexpress a mutant form of GK with increased enzymatic activity. Thesepatients exhibit a fasting hypoglycemia associated with aninappropriately elevated level of plasma insulin (Glaser, B., Kesavan,P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). Whilemutations of the GK gene are not found in the majority of patients withtype II diabetes, compounds that activate GK and, thereby, increase thesensitivity of the GK sensor system will still be useful in thetreatment of the hyperglycemia characteristic of all type II diabetes.Glucokinase activators will increase the flux of glucose metabolism inβ-cells and hepatocytes, which will be coupled to increased insulinsecretion. Such agents would be useful for treating type II diabetes.Several GK activators are known, see, for example, US 2004/0014968(Hofmann-La Roche Inc.) and WO 2004/002481 (Novo Nordisk A/S)

SUMMARY OF THE INVENTION

In an aspect, the present invention provides novel 2,3-di-substitutedN-heteroaromatic propionamides or pharmaceutically acceptable saltsthereof that are useful as glucokinase activators.

In another aspect, the present invention provides novel pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a novel method oftreating type II diabetes comprising administering to a patient in needthereof a therapeutically effective amount of at least one compound ofthe present invention or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a novel method oftreating a condition or disease, comprising administering to a patientin need thereof a therapeutically effective amount of at least onecompound of the present invention or a pharmaceutically acceptable saltthereof, wherein the condition or disorder is selected from a metabolicdisorder, blood glucose lowering, hyperglycemia, impaired glucosetolerance (IGT), Syndrome X, Polycystic Ovarian Syndrome, impairedfasting glucose (IFG), type I diabetes, delaying the progression ofimpaired glucose tolerance (IGT) to type II diabetes, delaying theprogression of non-insulin requiring type II diabetes to insulinrequiring type II diabetes, dyslipidemia, hyperlipidemia, hypertension,treatment or prophylaxis of obesity, lowering of food intake, appetiteregulation, regulating feeding behaviour, and enhancing the secretion ofenteroincretins.

In another aspect, the present invention provides novel2,3-di-substituted N-heteroaromatic propionamides for use in therapy.

In another aspect, the present invention provides the use of novel2,3-di-substituted N-heteroaromatic propionamides for the manufacture ofa medicament for the treatment of type II diabetes.

In another aspect, the present invention provides the use of novel2,3-di-substituted N-heteroaromatic propionamides for the manufacture ofa medicament for the treatment of a condition or disorder selected froma metabolic disorder, blood glucose lowering, hyperglycemia, impairedglucose tolerance (IGT), Syndrome X, Polycystic Ovarian Syndrome,impaired fasting glucose (IFG), type I diabetes, delaying theprogression of impaired glucose tolerance (IGT) to type II diabetes,delaying the progression of non-insulin requiring type II diabetes toinsulin requiring type II diabetes, dyslipidemia, hyperlipidemia,hypertension, treatment or prophylaxis of obesity, lowering of foodintake, appetite regulation, regulating feeding behaviour, and enhancingthe secretion of enteroincretins.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formula I:

wherein ring A is a 5-6 membered heteroaromatic ring, orpharmaceutically acceptable salts thereof, are expected to be effectiveglucokinase activators.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the present invention provides a novel compound offormula I:

wherein, the * indicates an asymmetric atom;

R¹ is selected from H, Cl, F, Br, I, NH₂, —NHOH, —CN, —NO₂, C₁₋₆ alkyl,—OR⁵, —C(O)OR⁶, perfluoro-C₁₋₆ alkyl, C₁₋₆ alkyl-S—, perfluoro-C₁₋₆alkyl-S—, C₁₋₆ alkyl-SO₂—, perfluoro-C₁₋₆ alkyl-SO₂—, C₁₋₆ alkoxy-C₁₋₆alkyl-SO₂—, C₁₋₆ alkyl-S(O)—, and —SO₂NR¹³R¹⁴;

R² is selected from H, Cl, F, Br, I, NH₂, —NHOH, —CN, —NO₂, C₁₋₆ alkyl,—OR⁵, —C(O)OR⁶, perfluoro-C₁₋₆ alkyl, C₁₋₆ alkyl-S—, perfluoro-C₁₋₆alkyl-S—, C₁₋₆ alkyl-SO₂—, C₃₋₆ cycloalkyl-SO₂—, perfluoro-C₁₋₆alkyl-SO₂—, C₁₋₆ alkoxy-C₁₋₆ alkyl-SO₂—, C₁₋₆ alkyl-S(O)—, and —SO₂NH₂;

R³ is selected from C₃₋₇ cycloalkyl and C₂₋₄ alkyl;

ring A is a mono-substituted or a di-substituted 5-6 memberedheteroaromatic ring consisting of, in addition to the C═N shown, carbonatoms and 0-2 heteroatoms selected from S(O)_(p), O, and N;

p is selected from 0, 1, and 2;

when ring A is mono-substituted; the substituent is selected from: —CHO;—(CH₂)_(n)—C₃₋₈ cycloalkyl; —(CH₂)_(n)-aryl; —(CH₂)_(n)-5-10 memberedheterocycle consisting of carbon atoms and 1-3 heteroatoms selected fromS(O)_(p), O, and N; —(CH₂)_(n)-5-10 membered heteroaryl consisting ofcarbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and N;—(CH₂)_(n)—C(O)R⁷; —(CH₂)_(n)—OC(O)R⁷; —(CH₂)_(n)—S(O)_(p)R⁷;—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—C₃₋₈ cycloalkyl;—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)-aryl; —(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)-5-10membered heterocycle consisting of carbon atoms and 1-3 heteroatomsselected from S(O)_(p), O, and N; —(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)-5-10membered heteroaryl consisting of carbon atoms and 1-3 heteroatomsselected from S(O)_(p), O, and N; —(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—NR¹⁰R¹¹;—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—C(O)NR¹⁰R¹¹;—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—C(O)OR⁷;—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—C(O)OH; —O—(CH₂)_(n)—C₃₋₈ cycloalkyl;—O—(CH₂)_(n)-aryl; —O—(CH₂)_(n)-5-10 membered heterocycle consisting ofcarbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and N;—O—(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and 1-3heteroatoms selected from S(O)_(p), O, and N; —S(O)₂—NR¹⁰R¹¹; —NR⁸R⁹;and —NHC(O)R⁷; wherein each of these substituents is substituted with0-2 R¹² and provided that R⁸ and R⁹ cannot both be H;

when ring A is di-substituted; the substituent is selected from: Cl; F;Br; I; —CN; —NO₂; CF₃; —SCN; —CHO; C₁₋₈ alkyl; —(CH₂)_(n)—C₃₋₈cycloalkyl; —(CH₂)_(n)-aryl; —(CH₂)_(n)-5-10 membered heterocycleconsisting of carbon atoms and 1-3 heteroatoms selected from S(O)_(p),O, and N; —(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atomsand 1-3 heteroatoms selected from S(O)_(p), O, and N;—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—NR¹⁰R¹¹;—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—C(O)NR¹⁰R¹¹;—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—C(O)OR⁷;—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—C(O)OH; —(CH₂)_(n)—C(O)R⁷;—(CH₂)_(n)—C(O)OR⁷; —(CH₂)_(n)—C(O)OH; (CH₂)_(n)—OC(O)R⁷;—(CH₂)_(n)—S(O)_(p)R⁷; —(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—C₃₋₈ cycloalkyl;—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)-aryl; —(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)-5-10membered heterocycle consisting of carbon atoms and 1-3 heteroatomsselected from S(O)_(p), O, and N; —(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)-5-10membered heteroaryl consisting of carbon atoms and 1-3 heteroatomsselected from S(O)_(p), O, and N; —(CH₂)_(n)—OH; —(CH₂)_(n)—OR′;—O—(CH₂)_(n)—C₃₋₈ cycloalkyl; —O—(CH₂)_(n)-aryl;—O—(CH₂)_(n)-heterocyclyl; —O—(CH₂)_(n)-5-10 membered heteroarylconsisting of carbon atoms and 1-3 heteroatoms selected from S(O)_(p),O, and N; —S(O)₂—NR¹⁰R¹¹; —(CH₂)_(n)—NR⁸R⁹; and —NHC(O)R⁷; wherein eachof these substituents is substituted with 0-2 R¹²;

n, at each occurrence, is independently selected from 0, 1, 2, 3, 4, 5,and 6;

R⁵, at each occurrence, is independently selected from H, C₁₋₆ alkyl,and perfluoro-C₁₋₆ alkyl;

R⁶, at each occurrence, is independently C₁₋₆ alkyl;

R⁷, at each occurrence, is independently selected from C₁₋₈ alkyl andC₃₋₈ cycloalkyl;

R⁸, at each occurrence, is independently selected from H, C₁₋₈ alkyl,—(CH₂)_(n)—OH, —(CH₂)_(n)—C(O)OH, aryl, and 5-10 membered heteroarylconsisting of carbon atoms and 1-3 heteroatoms selected from S(O)_(p),O, and N;

R⁹, at each occurrence, is independently selected from H, C₁₋₈ alkyl,—(CH₂)_(n)—OH, —(CH₂)_(n)—C(O)OH, aryl, and 5-10 membered heteroarylconsisting of carbon atoms and 1-3 heteroatoms selected from S(O)_(p),O, and N;

alternatively, R⁸ and R⁹, together with the nitrogen to which they areattached form a 5-6 membered heterocycle, consisting of, in addition tothe nitrogen atom to which R⁸ and R⁹ are attached, carbon atoms and 0-2heteroatoms selected from S(O)_(p), O, and N;

R¹⁰, at each occurrence, is independently selected from H; C₁₋₆ alkyl;—(CH₂)_(n)—OH; —(CH₂)_(n)—C(O)OH; —(CH₂)_(n)—C₃₋₈ cycloalkyl;—(CH₂)_(n)-aryl; —(CH₂)_(n)-5-10 membered heterocycle consisting ofcarbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and N;—(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and 1-3heteroatoms selected from S(O)_(p), O, and N; —(CH₂)_(n)—NHR⁷; and—(CH₂)_(n)—NR⁷R⁷;

R¹¹, at each occurrence, is independently selected from H; C₁₋₆ alkyl;—(CH₂)_(n)—OH; —(CH₂)_(n)—C(O)OH; —(CH₂)_(n)—C₃₋₈ cycloalkyl;—(CH₂)_(n)-aryl; —(CH₂)_(n)-5-10 membered heterocycle consisting ofcarbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and N;—(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and 1-3heteroatoms selected from S(O)_(p), O, and N; —(CH₂)_(n)—NHR⁷; and—(CH₂)_(n)—NR⁷R⁷;

alternatively, R¹⁰ and R¹¹, together with the nitrogen to which they areattached form a 5-6 membered heterocycle, consisting of, in addition tothe nitrogen atom to which R¹⁰ and R¹¹ are attached, carbon atoms and0-2 heteroatoms selected from S(O)_(p), O, and N;

R¹², at each occurrence, is independently selected from C₁₋₆ alkyl, Cl,F, Br, I, NO₂, —CN, —(CH₂)_(n)—OH, —(CH₂)_(n)—C(O)OH, —(CH₂)_(n)—C(O)OR,NR⁸R⁹, NHS(O)₂CH₃, S(O)₂CH₃, and S(O)₂NH₂;

R¹³, at each occurrence, is independently selected from H and C₁₋₄alkyl; and,

R¹⁴, at each occurrence, is independently selected from H and C₁₋₄alkyl.

In another embodiment, the present invention provides a novel compoundwherein ring A is mono-substituted and the substituent is selected from:—(CH₂)_(n)—S(O)_(p)—(CH₂)₁₋₄—C(O)OR⁷;—(CH₂)_(n)—S(O)_(p)—(CH₂)₁₋₄—C(O)OH;—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—C(O)NR¹⁰R¹¹; and —(CH₂)_(n)-5-6 memberedheterocycle consisting of carbon atoms and 1-3 heteroatoms selected fromS(O)_(p), O, and N and is substituted with 0-1 C₁₋₄ alkyl; and,

R⁷, at each occurrence, is independently selected from C₁₋₄ alkyl andC₃₋₆ cycloalkyl.

In another embodiment, the present invention provides a novel compoundwherein ring A is di-substituted, the substituent is selected from: Cl;CF₃; C₁₋₄ alkyl; —(CH₂)_(n)—C(O)OR⁷; —(CH₂)_(n)—C(O)OH;—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—C(O)NR¹⁰R¹¹; and—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)-5-6 membered heterocycle consisting ofcarbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and N and issubstituted with 0-1 C₁₋₄ alkyl; and,

R⁷, at each occurrence, is independently selected from C₁₋₄ alkyl andC₃₋₆ cycloalkyl.

In another embodiment, the present invention provides a novel compoundwherein R⁸ and R⁹, together with the nitrogen to which they are attachedform a heterocycle selected from: piperazine, homopiperazine, andmorpholine.

In another embodiment, the present invention provides a novel compoundwherein R¹⁰ and R¹¹, together with the nitrogen to which they areattached form a heterocycle selected from: piperidine, piperazine,homopiperazine, pyrrolidine, and morpholine.

In another embodiment, the present invention provides a novel compoundwherein the asymmetric carbon shown is in the R configuration.

In another embodiment, the present invention provides a novel compoundwherein R³ is selected from C₃₋₅ cycloalkyl.

In another embodiment, the present invention provides a novel compoundwherein R³ is cyclopentyl.

In another embodiment, the present invention provides a novel compoundwherein ring A is thiazole.

In another embodiment, the present invention provides a novel compoundwherein

R¹ is selected from H, CI, F, Br, I, perfluoro-C₁₋₆ alkyl, NO₂, NH₂,C₁₋₆ alkyl-SO₂—, and —SO₂NR¹³R¹⁴; and,

R² is selected from H, Cl, F, Br, I, perfluoro-C₁₋₆ alkyl, NO₂, NH₂,C₁₋₆ alkyl-SO₂—, and —SO₂NR¹³R¹⁴.

In another embodiment, the present invention provides a novel compoundwherein R² is C₁₋₆ alkyl-SO₂—.

In another embodiment, the present invention provides a novel compoundwherein R¹ and R² are both Cl.

In another embodiment, the present invention provides a novel compoundwherein R¹ is H and R² is C₁₋₆ alkyl-SO₂—.

In another embodiment, the present invention provides a novel compoundwherein R¹ is selected from C₁, CF₃, and CH₃ and R² is C₁₋₆ alkyl-SO₂—.

In another embodiment, the present invention provides a novel compoundwherein R¹ is H and R² is CH₃—SO₂—.

In another embodiment, the present invention provides a novel compoundwherein the compound is selected from:

-   {2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-acetic    acid ethyl ester;-   3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-propionamide;-   3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(4-methyl-piperazin-1-yl)thiazol-2-yl]-propionamide;-   {2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic    acid ethyl ester;-   {5-Chloro-2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-acetic    acid ethyl ester;-   {2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-acetic    acid;-   {2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic    acid;-   {5-Chloro-2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-acetic    acid;-   3-Cyclopentyl-N-[5-(2-diethylaminoethylsulfanyl)thiazol-2-yl]-2-(4-methanesulfonylphenyl)propionamide;    and,-   3-Cyclopentyl-N-[5-(methylsulfanyl)thiazol-2-yl]-2-(4-methanesulfonylphenyl)propionamide;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a novel compoundwherein the compound is selected from:

-   (R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-acetic    acid ethyl ester;-   (R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[4-methyl-5-(4-methyl-piperazine-1-sulfonyl)thiazol-2-yl]-propionamide;-   (R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(4-methyl-piperazin-1-yl)-thiazol-2-yl]-propionamide;-   (R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic    acid ethyl ester;-   (R)-{5-Chloro-2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-4-yl}-acetic    acid ethyl ester;-   (R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-acetic    acid;-   (R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic    acid;-   (R)-{5-Chloro-2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-4-yl}-acetic    acid;-   (R)-3-cyclopentyl-N-[5-(2-diethylaminoethylsulfanyl)thiazol-2-yl]-2-(4-methanesulfonylphenyl)propionamide;    and,-   (R)-3-cyclopentyl-N-[5-(methylsulfanyl)thiazol-2-yl]-2-(4-methanesulfonylphenyl)propionamide;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a novelpharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a compound of the present invention or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the present invention provides a novel method oftreating type II diabetes, comprising: administering to a subject inneed thereof a therapeutically effective amount of a compound of thepresent invention.

In another embodiment, the present invention provides a novel method oftreating a condition or disorder, comprising: administering to a subjectin need thereof a therapeutically effective amount of a compound of thepresent invention, wherein the condition or disorder is selected from ametabolic disorder, blood glucose lowering, hyperglycemia, impairedglucose tolerance (IGT), Syndrome X, Polycystic Ovarian Syndrome,impaired fasting glucose (IFG), type I diabetes, delaying theprogression of impaired glucose tolerance (IGT) to type II diabetes,delaying the progression of non-insulin requiring type II diabetes toinsulin requiring type II diabetes, dyslipidemia, hyperlipidemia,hypertension, treatment or prophylaxis of obesity, lowering of foodintake, appetite regulation, regulating feeding behaviour, and enhancingthe secretion of enteroincretins.

In another aspect the invention provides a compound of formula I:

wherein, the * indicates an asymmetric atom;

-   R¹ is selected from H, Cl, F, Br, I, NH₂, —NHOH, —CN, —NO₂, C₁₋₆    alkyl, —OR⁵, C(O)OR⁶, perfluoro-C₁₋₆ alkyl, C₁₋₆ alkyl-S—,    perfluoro-C₁₋₆ alkyl-S—, C₁₋₆ alkyl-SO₂—, perfluoro-C₁₋₆ alkyl-SO₂—,    C₁₋₆ alkoxy-C₁₋₆ alkyl-SO₂—, C₁₋₆ alkyl-S(O)—, and —SO₂NR¹³R¹⁴;-   R² is selected from H, Cl, F, Br, I, NH₂, —NHOH, —CN, —NO₂, C₁₋₆    alkyl, —OR⁵, C(O)OR⁶, perfluoro-C₁₋₆ alkyl, C₁₋₆ alkyl-S—,    perfluoro-C₁₋₆ alkyl-S—, C₁₋₆ alkyl-SO₂—, C₃₋₆ cycloalkyl-SO₂—,    perfluoro-C₁₋₆ alkyl-SO₂—, C₁₋₆ alkoxy-C₁₋₆ alkyl-SO₂—, C₁₋₆    alkyl-S(O)—, and —SO₂NH₂;-   R³ is selected from C₃₋₇ cycloalkyl and C₂₋₄ alkyl;-   ring A is a mono-substituted or a di-substituted 5-6 membered    heteroaromatic ring consisting of, in addition to the C═N shown,    carbon atoms and 0-2 heteroatoms selected from S(O)_(p), O, and N;-   when ring A is mono-substituted; the substituent is selected from:    —CHO; —SCN, —(CH₂)_(n)—C₃₋₈ cycloalkyl; —(CH₂)_(n)-aryl;    —(CH₂)_(n)-5-10 membered heterocycle consisting of carbon atoms and    1-3 heteroatoms selected from S(O)_(p), O, and N; —(CH₂)_(n)-5-10    membered heteroaryl consisting of carbon atoms and 1-3 heteroatoms    selected from S(O)_(p), O, and N; —(CH₂)_(n)—C(O)R⁷;    —(CH₂)_(n)—OC(O)R⁷; —(CH₂)_(n)—S(O)_(p)R⁷;    —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)—C₃₋₈ cycloalkyl;    —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)-aryl;    —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)-5-10 membered heterocycle consisting    of carbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and    N; —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)-5-10 membered heteroaryl consisting    of carbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and    N; —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)—NR¹⁰R¹¹;    —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)—C(O)NR¹⁰R¹¹;    —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)—C(O)OR⁷;    —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)—C(O)OH; —O—(CH₂)_(n)—C₃₋₈ cycloalkyl;    —O—(CH₂)_(n)-aryl; —O—(CH₂)_(n)-5-10 membered heterocycle consisting    of carbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and    N; —O—(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms    and 1-3 heteroatoms selected from S(O)_(p), O, and N;    —S(O)_(p)—(CH₂)_(n), —S(O)₂—NR¹⁰R¹¹; —NR⁸R⁹; and —NHC(O)R⁷; wherein    each of these substituents is substituted with 0-2 R¹² and provided    that R⁸ and R⁹ cannot both be H;-   when ring A is di-substituted; the substituent is selected from: Cl;    F; Br; I; —CN; —NO₂; CF₃; —SCN; —CHO; C₁₋₈ alkyl; —(CH₂)_(n)—C₃₋₈    cycloalkyl; —(CH₂)_(n)-aryl; —(CH₂)_(n)-5-10 membered heterocycle    consisting of carbon atoms and 1-3 heteroatoms selected from    S(O)_(p), O, and N; —(CH₂)_(n)-5-10 membered heteroaryl consisting    of carbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and    N; —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)—NR¹⁰R¹¹;    —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)—C(O)NR¹⁰R¹¹;    —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)—C(O)OR⁷;    —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)—C(O)OH; —(CH₂)_(n)—C(O)R⁷;    —(CH₂)_(n)—C(O)OR⁷; —(CH₂)_(n)—C(O)OH; —(CH₂)_(n)—OC(O)R⁷;    —(CH₂)_(n)—S(O)_(p)R⁷; —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)—C₃₋₈    cycloalkyl; —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)-aryl;    —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)-5-10 membered heterocycle consisting    of carbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and    N; —(CH₂)_(m)—S(O)_(p)—(CH₂)_(n)-5-10 membered heteroaryl consisting    of carbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and    N; —(CH₂)_(n)—OH; —(CH₂)_(n)—OR′; —O—(CH₂)_(n)—C₃₋₈ cycloalkyl;    —O—(CH₂)_(n)-aryl; —O—(CH₂)_(n)-heterocyclyl; —O—(CH₂)_(n)-5-10    membered heteroaryl consisting of carbon atoms and 1-3 heteroatoms    selected from S(O)_(p), O, and N; —S(O)₂—NR¹⁰R¹¹; —(CH₂)_(n)—NR⁸R⁹;    and —NHC(O)R⁷; wherein each of these substituents is substituted    with 0-2 R¹²;-   R⁵, at each occurrence, is independently selected from H, C₁₋₆    alkyl, and perfluoro-C₁₋₆ alkyl;-   R⁶, at each occurrence, is independently C₁₋₆ alkyl;-   R⁷, at each occurrence, is independently selected from C₁₋₈ alkyl    and C₃₋₈ cycloalkyl;-   R⁸, at each occurrence, is independently selected from H, C₁₋₈    alkyl, —(CH₂)_(n)—OH, (CH₂)_(n)—C(O)OH, aryl, and 5-10 membered    heteroaryl consisting of carbon atoms and 1-3 heteroatoms selected    from S(O)_(p), O, and N;-   R⁹, at each occurrence, is independently selected from H, C₁₋₈    alkyl, —(CH₂)_(n)—OH, —(CH₂)_(n)—C(O)OH, aryl, and 5-10 membered    heteroaryl consisting of carbon atoms and 1-3 heteroatoms selected    from S(O)_(p), O, and N;-   alternatively, R⁸ and R⁹, together with the nitrogen to which they    are attached form a 5-6 membered heterocycle, consisting of, in    addition to the nitrogen atom to which R⁸ and R⁹ are attached,    carbon atoms and 0-2 heteroatoms selected from S(O)_(p), O, and N;-   R¹⁰, at each occurrence, is independently selected from H; C₁₋₆    alkyl; —(CH₂)_(n)—OH; —(CH₂)_(n)—C(O)OH; —(CH₂)_(n)—C₃₋₈ cycloalkyl;    —(CH₂)_(n)-aryl; —(CH₂)_(n)-5-10 membered heterocycle consisting of    carbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and N;    —(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and    1-3 heteroatoms selected from S(O)_(p), O, and N; —(CH₂)_(n)—NHR⁷;    and —(CH₂)_(n)—NR⁷R⁷;-   R¹¹, at each occurrence, is independently selected from H; C₁₋₆    alkyl; —(CH₂)_(n)—OH; —(CH₂)_(n)—C(O)OH; —(CH₂)_(n)—C₃₋₈ cycloalkyl;    —(CH₂)_(n)-aryl; —(CH₂)_(n)-5-10 membered heterocycle consisting of    carbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and N;    —(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and    1-3 heteroatoms selected from S(O)_(p), O, and N; —(CH₂)_(n)—NHR⁷;    and —(CH₂)_(n)—NR⁷R⁷;-   alternatively, R¹⁰ and R¹¹, together with the nitrogen to which they    are attached form a 5-6 membered heterocycle, consisting of, in    addition to the nitrogen atom to which R¹⁰ and R¹¹ are attached,    carbon atoms and 0-2 heteroatoms selected from S(O)_(p), O, and N;    and wherein the heterocycle thus formed is substituted with 0-2 R¹²;-   R¹², at each occurrence, is independently selected from C₁₋₆ alkyl,    Cl, F, Br, I, NO₂, —CN, —(CH₂)_(n)—OH, —(CH₂)_(n)—C(O)OH,    —(CH₂)_(n)—C(O)OR, NR⁸R⁹, NHS(O)₂CH₃, S(O)₂CH₃, and S(O)₂NH₂;-   R¹³, at each occurrence, is independently selected from H and C₁₋₄    alkyl;-   R¹⁴, at each occurrence, is independently selected from H and C₁₋₄    alkyl;-   p, at each occurrence, is selected from 0, 1, and 2;-   n, at each occurrence, is independently selected from 0, 1, 2, 3, 4,    5, and 6; and-   m, at each occurrence, is independently selected from 0, 1, and 2.

In one embodiment hereof ring A is mono-substituted and the substituentis selected from: —(CH₂)₀₋₂—S(O)_(p)—(CH₂)₁₋₄—C(O)OR⁷;—(CH₂)₀₋₂—S(O)_(p)—(CH₂)₁₋₄—C(O)OH;—(CH₂)₀₋₂—S(O)_(p)—(CH₂)_(n)—NR¹⁰R¹¹,—(CH₂)₀₋₂—S(O)_(p)—(CH₂)_(n)—C(O)NR¹⁰R¹¹; and —(CH₂)_(n)-5-6 memberedheterocycle consisting of carbon atoms and 1-3 heteroatoms selected fromS(O)_(p), O, and N and is substituted with 0-1 C₁₋₄ alkyl; and,

-   R⁷, at each occurrence, is independently selected from C₁₋₄ alkyl    and C_(m) cycloalkyl.

In another embodiment hereof ring A is mono-substituted and thesubstituent is selected from: —S(O)₂—CH₂—C(O)OR⁷; —S(O)₂—CH₂—C(O)OH;—S—CH₂—C(O)OR⁷; —S—CH₂—CH₂—C(O)OR⁷; —S—CH₂—C(O)OH—S—CH₂—CH₂—C(O)OH;—S—(CH₂)₂—NR¹⁰R¹¹; —S—CH₂—C(O)NR¹⁰R¹¹; and piperazine; and,

-   R⁷, at each occurrence, is independently selected from C₁₋₂ alkyl.

In another embodiment hereof ring A is di-substituted, the substituentis selected from: Cl; CF₃, C₁₋₄ alkyl; —(CH₂)_(n)—C(O)OR⁷;—(CH₂)_(n)—C(O)OH; —(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—C(O)NR¹⁰R¹¹; and—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)-5-6 membered heterocycle consisting ofcarbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and N and issubstituted with 0-1 C₁₋₄ alkyl; and,

R⁷, at each occurrence, is independently selected from C₁₋₄ alkyl andC_(m) cycloalkyl.

In another embodiment hereof ring A is di-substituted, the substituentis selected from: Cl; CH₃; —CH₂—C(O)OR⁷; —CH₂—C(O)OH; and—S(O)₂-piperazine optionally substituted with CH₃, and,

-   R⁷, at each occurrence, is independently selected from C₁₋₂ alkyl.

In another embodiment hereof m is 0.

In another embodiment hereof n is 1.

In another embodiment hereof n is 2.

In another embodiment hereof R⁸ and R⁹, together with the nitrogen towhich they are attached form a heterocycle selected from: piperazine,homopiperazine, and morpholine.

In another embodiment hereof R¹⁰ and R¹¹, together with the nitrogen towhich they are attached form a heterocycle selected from: piperidine,piperazine, homopiperazine, pyrrolidine, and morpholine.

In another embodiment hereof the asymmetric carbon shown is in the Rconfiguration.

In another embodiment hereof R³ is selected from C₃₋₅ cycloalkyl.

In another embodiment hereof R³ is cyclopentyl.

In another embodiment hereof ring A is thiazole.

In another embodiment hereof R¹ is selected from H, Cl, F, Br, I,perfluoro-C₁₋₆ alkyl, NO₂, NH₂, C₁₋₆ alkyl-SO₂—, and —SO₂NR¹³R¹⁴; and,

R² is selected from H, Cl, F, Br, I, perfluoro-C₁₋₆ alkyl, NO₂, NH₂,C₁₋₆ alkyl-SO₂—, and —SO₂NR¹³R¹⁴.

In another embodiment hereof R² is C₁₋₆ alkyl-SO₂—.

In another embodiment hereof R¹ and R² are both Cl.

In another embodiment hereof R¹ is H and R² is C₁₋₆ alkyl-SO₂—.

In another embodiment hereof R¹ is selected from C₁, CF₃, and CH₃ and R²is C₁₋₆ alkyl-SO₂—.

In another embodiment hereof R¹ is H and R² is CH₃—SO₂—.

In another embodiment hereof the compound is selected from:

-   {2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-acetic    acid ethyl ester-   3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-propionamide-   3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(4-methyl-piperazin-1-yl)-thiazol-2-yl]-propionamide-   {2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic    acid ethyl ester-   {5-Chloro-2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-acetic    acid ethyl ester-   {2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-acetic    acid{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-acetic    acid-   {5-Chloro-2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-acetic    acid-   (R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)propionamide-   (R)-3-Cyclopentyl-N-[5-(2-diethylamino-ethylsulfanyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phenyl)-propionamide-   (R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methylsulfanyl-thiazol-2-yl)propionamide-   3-Cyclopentyl-N-(5-diethylcarbamoylmethylsulfanyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide-   {2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-sulfonyl}-acetic    acid-   (R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic    acid ethyl ester-   (R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic    acid-   (R)-3-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-propionic    acid ethyl ester-   (R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-oxo-2-piperazin-1-ylethylsulfanyl)-thiazol-2-yl]-propionamide-   (R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-morpholin-4-yl-2-oxoethylsulfanyl)-thiazol-2-yl]-propionamide-   (R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-{5-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethylsulfanyl]-thiazol-2-yl}-propionamide-   (R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-oxo-2-piperidin-1-ylethylsulfanyl)-thiazol-2-yl]-propionamide-   (R)-3-Cyclopentyl-N-[5-(2-dimethylamino-ethylsulfanyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phenyl)-propionamide-   (R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-morpholin-4-ylethylsulfanyl)-thiazol-2-yl]-propionamide-   (R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-piperidin-1-yl-ethylsulfanyl)thiazol-2-yl]-propionamide-   (R)-3-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-propionic    acid    or a pharmaceutically acceptable salt thereof.

In an additional aspect the invention provides a pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and acompound of the invention or a pharmaceutically acceptable salt thereof.

In an additional aspect the invention provides a method of treating typeII diabetes, comprising: administering to a subject in need thereof atherapeutically effective amount of a compound of the invention.

In an additional aspect the invention provides a method of treating acondition or disorder, comprising: administering to a subject in needthereof a therapeutically effective amount of a compound of theinvention, wherein the condition or disorder is selected from ametabolic disorder, blood glucose lowering, hyperglycemia, impairedglucose tolerance (IGT), Syndrome X, Polycystic Ovarian Syndrome,impaired fasting glucose (IFG), type I diabetes, delaying theprogression of impaired glucose tolerance (IGT) to type II diabetes,delaying the progression of non-insulin requiring type II diabetes toinsulin requiring type II diabetes, dyslipidemia, hyperlipidemia,hypertension, treatment or prophylaxis of obesity, lowering of foodintake, appetite regulation, regulating feeding behaviour, and enhancingthe secretion of enteroincretins.

In the present invention, there is an asymmetric center in the compoundof formula I that is represented by an asterisk (*). As a result,compounds of the present invention may be racemic or have thestereochemistry shown in formulae Ia and Ib.

Preferably, the compounds of the present invention are in the Rconfiguration (e.g., formula Ia).

In another embodiment of the present invention, the present compoundsare administered in combination with one or more further activesubstances in any suitable ratios. When used in combination with one ormore further active substances, the combination of compounds ispreferably a synergistic combination. Synergy α-curs when the effect ofthe compounds when administered in combination is greater than theadditive effect of the compounds when administered as a single agent. Ingeneral, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Such further active agentsmay be selected from antidiabetic agents, antihyperlipidemic agents,anti-obesity agents, antihypertensive agents, and agents for thetreatment of complications resulting from or associated with diabetes.

Suitable antidiabetic agents include insulin, GLP-1 (glucagon likepeptide-1) derivatives such as those disclosed in WO 98/08871 (NovoNordisk A/S), which is incorporated herein by reference, as well asorally active hypoglycemic agents.

Suitable orally active hypoglycemic agents preferably includeimidazolines, sulfonylureas, biguanides, meglitinides,oxadiazolidinediones, thiazolidinediones, insulin sensitizers,α-glucosidase inhibitors, agents acting on the ATP-dependent potassiumchannel of the pancreatic β-cells e.g., potassium channel openers suchas those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (NovoNordisk A/S) which are incorporated herein by reference, potassiumchannel openers, such as ormitiglinide, potassium channel blockers suchas nateglinide or BTS-67582, glucagon antagonists such as thosedisclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and AgouronPharmaceuticals, Inc.), all of which are incorporated herein byreference, GLP-1 agonists such as those disclosed in WO 00/42026 (NovoNordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporatedherein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase(protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymesinvolved in stimulation of gluconeogenesis and/or glycogenolysis,glucose uptake modulators, GSK-3 (glycogen synthase kinase-3)inhibitors, compounds modifying the lipid metabolism such asantihyperlipidemic agents and antilipidemic agents, compounds loweringfood intake, and PPAR (peroxisome proliferator-activated receptor) andRXR (retinoid X receptor) agonists such as ALRT-268, LG-1268 or LG-1069.

In another embodiment of the present invention, the present compoundsare administered in combination with a sulphonylurea, e.g., tolbutamide,chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride,glicazide, or glyburide.

In another embodiment of the present invention, the present compoundsare administered in combination with a biguanide, e.g., metformin.

In another embodiment of the present invention, the present compoundsare administered in combination with a meglitinide, e.g., repaglinide orsenaglinide/nateglinide.

In another embodiment of the present invention, the present compoundsare administered in combination with a thiazolidinedione insulinsensitizer, e.g., troglitazone, ciglitazone, pioglitazone,rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037,T 174, the compounds disclosed in WO 97/41097 (DRF-2344), WO 97/41119,WO 97/41120, WO 00/41121. and WO 98/45292 (Dr. Reddy's ResearchFoundation), which are incorporated herein by reference.

In another embodiment of the present invention, the present compoundsmay be administered in combination with an insulin sensitizer, e.g., GI262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544,CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516, thecompounds disclosed in WO 99/19313 (NN622/DRF-2725), WO 00/50414, WO00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy's Research Foundation), WO00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190, and WO00/63189 (Novo Nordisk A/S), which are incorporated herein by reference.

In another embodiment of the present invention, the present compoundsare administered in combination with an α-glucosidase inhibitor, e.g.,voglibose, emiglitate, miglitol, or acarbose.

In another embodiment of the present invention, the present compoundsare administered in combination with a glycogen phosphorylase inhibitor,e.g., the compounds described in WO 97/09040 (Novo Nordisk A/S).

In another embodiment of the present invention, the present compoundsare administered in combination with an agent acting on theATP-dependent potassium channel of the pancreatic β-cells, e.g.,tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582, orrepaglinide.

In another embodiment of the present invention, the present compoundsare administered in combination with nateglinide.

In another embodiment of the present invention, the present compoundsare administered in combination with an antihyperlipidemic agent or aantilipidemic agent, e.g., cholestyramine, colestipol, clofibrate,gemfibrozil, lovastatin, pravastatin, simvastatin, probucol, ordextrothyroxine.

In another embodiment, the compounds of the present invention may beadministered in combination with one or more anti-obesity agents orappetite regulating agents. Such agents may be selected from the groupconsisting of CART (cocaine amphetamine regulated transcript) agonists,NPY (neuropeptide Y) antagonists, MC3 (melanocortin 3) agonists, MC4(melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosisfactor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP(corticotropin releasing factor binding protein) antagonists, urocortinagonists, (33 adrenergic agonists such as CL-316243, AJ-9677, GW-0604,LY362884, LY377267 or AZ-40140, MSH (melanocyte-stimulating hormone)agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK(cholecystokinin) agonists, serotonin reuptake inhibitors (fluoxetine,seroxat or citalopram), serotonin and norepinephrine reuptakeinhibitors, 5HT (serotonin) agonists, bombesin agonists, galaninantagonists, growth hormone, growth factors such as prolactin orplacental lactogen, growth hormone releasing compounds, TRH(thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncouplingprotein 2 or 3) modulators, leptin agonists, DA (dopamine) agonists(bromocriptin, doprexin), lipase/amylase inhibitors, PPAR modulators,RXR modulators, TR β agonists, adrenergic CNS stimulating agents, AGRP(agouti related protein) inhibitors, H3 histamine antagonists such asthose disclosed in WO 00/42023, WO 00/63208 and WO 00/64884, which areincorporated herein by reference, exendin-4, GLP-1 agonists, ciliaryneurotrophic factor, and oxyntomodulin. Further anti-obesity agents arebupropion (antidepressant), topiramate (anticonvulsant), ecopipam(dopamine D1/D5 antagonist), and naltrexone (opioid antagonist).

In another embodiment of the present invention, the anti-obesity agentis leptin.

In another embodiment of the present invention, the anti-obesity agentis a serotonin and norepinephrine reuptake inhibitor, e.g., sibutramine.

In another embodiment of the present invention, the anti-obesity agentis a lipase inhibitor, e.g., orlistat.

In another embodiment of the present invention, the anti-obesity agentis an adrenergic CNS stimulating agent, e.g., dexamphetamine,amphetamine, phentermine, mazindol phendimetrazine, diethylpropion,fenfluramine, or dexfenfluramine.

In another embodiment of the present invention, the present compoundsmay be administered in combination with one or more antihypertensiveagents. Examples of antihypertensive agents are n-blockers such asalprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE(angiotensin converting enzyme) inhibitors such as benazepril,captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril,calcium channel blockers such as nifedipine, felodipine, nicardipine,Isradipine, nimodipine, diltiazem and verapamil, and α-blockers such asdoxazosin, urapidil, prazosin and terazosin. Further reference can bemade to Remington: The Science and Practice of Pharmacy, 19th Edition,Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

In another embodiment of the present invention, the present compoundsare administered in combination with insulin, insulin derivatives orinsulin analogues.

In another embodiment of the present invention, the insulin is aninsulin derivative is selected from the group consisting ofB29-N^(ε)-myristoyl-des(B30) human insulin, B29-N^(ε)-palmitoyl-des(B30)human insulin, B29-N^(ε)-myristoyl human insulin, B29-N^(ε)-palmitoylhuman insulin, B28-N^(ε)-myristoyl Lys^(B28) Pro^(B29) human insulin,B28-N^(ε)-palmitoyl Lys^(B28) Pro^(B29) human insulin,B30-N^(ε)-myristoyl-Thr^(B29)Lys^(B30) human insulin,B30-N^(ε)-palmitoyl-Thr^(B29)Lys^(B30) human insulin,B29-N^(ε)-(N-palmitoyl-γ-glutamyl)des(B30) human insulin,B29-N^(ε)-(N-lithocholyl-γ-glutamyl)-des(B30) human insulin,B29-N^(ε)-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N^(ε)-(ω-carboxyheptadecanoyl) human insulin.

In another embodiment of the present invention, the insulin derivativeis B29-N^(ε)-myristoyl-des(B30) human insulin.

In another embodiment of the present invention, the insulin is anacid-stabilised insulin. The acid-stabilised insulin may be selectedfrom analogues of human insulin having one of the following amino acidresidue substitutions:

-   -   A21G    -   A21G, B28K, B29P    -   A21G, B28D    -   A21G, B28E    -   A21G, B3K, B29E    -   A21G, desB27    -   A21G, B9E    -   A21G, B9D    -   A21G, B10E insulin.

In another embodiment of the present invention, the insulin is aninsulin analogue. The insulin analogue may be selected from the groupconsisting of: an analogue wherein position B28 is Asp, Lys, Leu, Val,or Ala and position B29 is Lys or Pro; des(B28-B30); des(B27); or,des(B30) human insulin.

In another embodiment the analogue is an analogue of human insulinwherein position B28 is Asp or Lys, and position B29 is Lys or Pro.

In another embodiment the analogue is des(B30) human insulin.

In another embodiment the insulin analogue is an analogue of humaninsulin wherein position B28 is Asp.

In another embodiment the analogue is an analogue wherein position B3 isLys and position B29 is Glu or Asp.

In another embodiment the GLP-1 derivative to be employed in combinationwith a compound of the present invention refers to GLP-1(1-37),exendin-4(1-39), insulinotropic fragments thereof, insulinotropicanalogues thereof and insulinotropic derivatives thereof. Insulinotropicfragments of GLP-1(1-37) are insulinotropic peptides for which theentire sequence can be found in the sequence of GLP-1(1-37) and where atleast one terminal amino acid has been deleted. Examples ofinsulinotropic fragments of GLP-1(1-37) are GLP-1(7-37) wherein theamino acid residues in positions 1-6 of GLP-1(1-37) have been deleted,and GLP-1(7-36) where the amino acid residues in position 1-6 and 37 ofGLP-1(1-37) have been deleted. Examples of insulinotropic fragments ofexendin-4(1-39) are exendin-4(1-38) and exendin-4(1-31). Theinsulinotropic property of a compound may be determined by in vivo or invitro assays well known in the art. For instance, the compound may beadministered to an animal and monitoring the insulin concentration overtime. Insulinotropic analogues of GLP-1(1-37) and exendin-4(1-39) referto the respective molecules wherein one or more of the amino acidsresidues have been exchanged with other amino acid residues and/or fromwhich one or more amino acid residues have been deleted and/or fromwhich one or more amino acid residues have been added with the provisothat said analogue either is insulinotropic or is a prodrug of aninsulinotropic compound. Examples of insulinotropic analogues ofGLP-1(1-37) are e.g. Met⁸-GLP-1(7-37) wherein the alanine in position 8has been replaced by methionine and the amino acid residues in position1 to 6 have been deleted, and Arg³⁴-GLP-1(7-37) wherein the valine inposition 34 has been replaced with arginine and the amino acid residuesin position 1 to 6 have been deleted. An example of an insulinotropicanalogue of exendin-4(1-39) is Ser²Asp³-exendin-4(1-39) wherein theamino acid residues in position 2 and 3 have been replaced with serineand aspartic acid, respectively (this particular analogue also beingknown in the art as exendin-3). Insulinotropic derivatives ofGLP-1(1-37), exendin-4(1-39) and analogues thereof are what the personskilled in the art considers to be derivatives of these peptides, i.e.,having at least one substituent which is not present in the parentpeptide molecule with the proviso that said derivative either isinsulinotropic or is a prodrug of an insulinotropic compound. Examplesof substituents are amides, carbohydrates, alkyl groups and lipophilicsubstituents. Examples of insulinotropic derivatives of GLP-1(1-37),exendin-4(1-39) and analogues thereof are GLP-1(7-36)-amide, Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37) andTyr³¹-exendin-4(1-31)-amide. Further examples of GLP-1(1-37),exendin-4(1-39), insulinotropic fragments thereof, insulinotropicanalogues thereof and insulinotropic derivatives thereof are describedin WO 98/08871, WO 99/43706, U.S. Pat. No. 5,424,286, and WO 00/09666.

In another embodiment of the present invention, the present compoundsare administered in combination with more than one of theabove-mentioned compounds, e.g. in combination with metformin and asulphonylurea such as glyburide; a sulphonylurea and acarbose;nateglinide and metformin; acarbose and metformin; a sulfonylurea,metformin and troglitazone; insulin and a sulfonylurea; insulin andmetformin; insulin, metformin and a sulfonylurea; insulin andtroglitazone; insulin and lovastatin; etc.

It should be understood that any suitable combination of the compoundsaccording to the invention with diet and/or exercise, one or more of theabove-mentioned compounds and optionally one or more other activesubstances are considered to be within the scope of the presentinvention. In another embodiment of the present invention, thepharmaceutical composition according to the present invention comprisese.g. a compound of the invention in combination with metformin and asulphonylurea such as glyburide; a compound of the invention incombination with a sulphonylurea and acarbose; nateglinide andmetformin; acarbose and metformin; a sulfonylurea, metformin andtroglitazone; insulin and a sulfonylurea; insulin and metformin;insulin, metformin and a sulfonylurea; insulin and troglitazone; insulinand lovastatin; etc.

Pharmaceutical Compositions

The compounds of the present invention may be administered alone or incombination with pharmaceutically acceptable carriers or excipients, ineither single or multiple doses. The pharmaceutical compositionsaccording to the invention may be formulated with pharmaceuticallyacceptable carriers or diluents as well as any other known adjuvants andexcipients in accordance with conventional techniques such as thosedisclosed in Remington: The Science and Practice of Pharmacy, 19^(th)Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,pulmonary, topical (including buccal and sublingual), transdermal,intracisternal, intraperitoneal, vaginal and parenteral (includingsubcutaneous, intramuscular, intrathecal, intravenous, and intradermal)route, the oral route being preferred. the preferred route will dependon the general condition and age of the subject to be treated, thenature of the condition to be treated, and the active ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosageforms such as hard or soft capsules, tablets, troches, dragees, pills,lozenges, powders and granules. Where appropriate, they can be preparedwith coatings such as enteric coatings or they can be formulated so asto provide controlled release of the active ingredient such as sustainedor prolonged release according to methods well known in the art. Liquiddosage forms for oral administration include solutions, emulsions,aqueous or oily suspensions, syrups, and elixirs. Pharmaceuticalcompositions for parenteral administration include sterile aqueous andnon-aqueous injectable solutions, dispersions, suspensions or emulsionsas well as sterile powders to be reconstituted in sterile injectablesolutions or dispersions prior to use. Depot injectable formulations arealso contemplated as being within the scope of the present invention.Other suitable administration forms include suppositories, sprays,ointments, cremes, gels, inhalants, dermal patches, implants, etc.

A typical oral dosage is in the range of from about 0.001 to about 100mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kgbody weight per day, and more preferred from about 0.05 to about 10mg/kg body weight per day administered in one or more dosages such as 1to 3 dosages. The exact dosage will depend upon the frequency and modeof administration, the sex, age, weight and general condition of thesubject treated, the nature and severity of the condition treated andany concomitant diseases to be treated and other factors evident tothose skilled in the art.

The formulations may conveniently be presented in unit dosage form bymethods known to those skilled in the art. A typical unit dosage formfor oral administration one or more times per day, such as 1 to 3 timesper day, may contain from 0.05 to about 1000 mg, preferably from about0.1 to about 500 mg, and more preferably from about 0.5 mg to about 200mg.

For parenteral routes such as intravenous, intrathecal, intramuscular,and similar administration, typically doses are in the order of abouthalf the dose employed for oral administration.

The compounds of this invention are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. Examples arean acid addition salt of a compound having the utility of a free baseand a base addition salt of a compound having the utility of a freeacid. The term “pharmaceutically acceptable salt(s)” refers to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid or byreacting the free acid with a suitable organic or inorganic base. When acompound according to the present invention contains a free base, suchsalts are prepared in a conventional manner by treating a solution orsuspension of the compound with a chemical equivalent of apharmaceutically acceptable acid. When a compound according to thepresent invention contains a free acid, such salts are prepared in aconventional manner by treating a solution or suspension of the compoundwith a chemical equivalent of a pharmaceutically acceptable base.Physiologically acceptable salts of a compound with a hydroxy groupinclude the anion of said compound in combination with a suitablecation, such as sodium or ammonium ion. Other salts which are notpharmaceutically acceptable may be useful in the preparation ofcompounds of the present invention and these form a further aspect ofthe present invention.

Representative examples of suitable inorganic acids includehydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitricacids, and the like. Representative examples of suitable organic acidsinclude formic, acetic, trichloroacetic, trifluoroacetic, propionic,benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic,malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic,methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic,bismethylene salicylic, ethanedisulfonic, gluconic, citraconic,aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, p-toluenesulfonic acids, and the like. Further examplesof pharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in J. Pharm. Sci.1977, 66, 2. Examples of metal salts include lithium, sodium, potassium,magnesium salts, and the like. Examples of ammonium and alkylatedammonium salts include ammonium, methylammonium, dimethylammonium,trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium,butylammonium, tetramethylammonium salts, and the like.

For parenteral administration, solutions of the novel compounds of theformula (I) in sterile aqueous solution, aqueous propylene glycol orsesame or peanut oil may be employed. Such aqueous solutions should besuitably buffered if necessary and the liquid diluent first renderedisotonic with sufficient saline or glucose. The aqueous solutions areparticularly suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The sterile aqueous media employed areall readily available by standard techniques known to those skilled inthe art.

Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solution and various organic solvents. Examplesof solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc,gelatine, agar, pectin, acacia, magnesium stearate, stearic acid andlower alkyl ethers of cellulose. Examples of liquid carriers are syrup,peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines,polyoxyethylene and water. Similarly, the carrier or diluent may includeany sustained release material known in the art, such as glycerylmonostearate or glyceryl distearate, alone or mixed with a wax. Thepharmaceutical compositions formed by combining the novel compounds ofthe present invention and the pharmaceutically acceptable carriers arethen readily administered in a variety of dosage forms suitable for thedisclosed routes of administration. The formulations may conveniently bepresented in unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules or tablets, eachcontaining a predetermined amount of the active ingredient, and whichmay include a suitable excipient. Furthermore, the orally availableformulations may be in the form of a powder or granules, a solution orsuspension in an aqueous or non-aqueous liquid, or an oil-in-water orwater-in-oil liquid emulsion.

Compositions intended for oral use may be prepared according to anyknown method, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxicpharmaceutically-acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example corn starch or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,356,108;4,166,452; and 4,265,874, incorporated herein by reference, to formosmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or a softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions may contain the active compounds in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatidesuch as lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more coloring agents,one or more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as a liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active compound inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring, and coloringagents may also be present.

The pharmaceutical compositions of the present invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, for example, olive oil or arachis oil, or a mineral oil, forexample a liquid paraffin, or a mixture thereof. Suitable emulsifyingagents may be naturally-occurring gums, for example gum acacia or gumtragacanth, naturally-occurring phosphatides, for example soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides, for example sorbitan monooleate, and condensationproducts of said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known methods using suitable dispersing orwetting agents and suspending agents described above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conveniently employed as solvent or suspending medium. For thispurpose, any bland fixed oil may be employed using synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

The compositions may also be in the form of suppositories for rectaladministration of the compounds of the present invention. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will thus melt in the rectum torelease the drug. Such materials include cocoa butter and polyethyleneglycols, for example.

For topical use, creams, ointments, jellies, solutions of suspensions,etc., containing the compounds of the present invention arecontemplated. For the purpose of this application, topical applicationsshall include mouth washes and gargles.

The compounds of the present invention may also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes may beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

In addition, some of the compounds of the present invention may formsolvates with water or common organic solvents. Such solvates are alsoencompassed within the scope of the present invention.

Thus, in a further embodiment, there is provided a pharmaceuticalcomposition comprising a compound according to the present invention, ora pharmaceutically acceptable salt, solvate, or prodrug thereof, and oneor more pharmaceutically acceptable carriers, excipients, or diluents.

If a solid carrier is used for oral administration, the preparation maybe tableted, placed in a hard gelatine capsule in powder or pellet formor it can be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will usually be from about 25 mg to about 1g. If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatine capsule or sterile injectable liquid suchas an aqueous or non-aqueous liquid suspension or solution.

A typical tablet that may be prepared by conventional tablettingtechniques may contain:

Core: Active compound (as free compound or salt thereof) 5.0 mg LactosumPh. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mgAmberlite ®IRP88* 1.0 mg Magnesii stearas Ph. Eur. q.s. Coating:Hydroxypropyl methylcellulose approx. 9 mg Mywacett 9-40 T** approx. 0.9mg Polacrillin potassium NF, tablet disintegrant, Rohm and Haas.**Acylated monoglyceride used as plasticizer for film coating.

If desired, the pharmaceutical composition of the present invention maycomprise a compound according to the present invention in combinationwith further active substances such as those described in the foregoing.

DEFINITIONS

As used herein, “substituted” signifies that one or more hydrogen atomsare replaced by the designated substituent. Only pharmaceutically stablecompounds are intended to be covered.

The present invention includes all isotopes of atoms occurring in thepresent compounds. Isotopes include those atoms having the same atomicnumber but different mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium. Isotopesof carbon include C-13 and C-14.

As used herein, “alkyl” includes both straight chain and branched alkylgroups having the designated number of carbon atoms (e.g., 1, 2, 3, 4,5, 6, 7, or 8). Examples of alkyl groups include, but are not limitedto, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl. Preferred alkyl groups are methyl and ethyl.

As used herein, “perfluoro-alkyl” means an alkyl group as defined abovewherein all of the hydrogens of the alkyl group are replaced by fluoro.Preferred perfluoro-alkyl groups include, but are not limited to,trifluoromethyl, pentafluoroethyl, and heptafluoropropyl.

As used herein, “alkoxy” signifies a lower alkyl group as defined abovelinked via an oxygen to the remainder of the molecule and includes bothstraight chain and branched chain alkyl groups having the designatednumber of carbon atoms. Examples of alkoxy include, but are not limitedto, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy,and t-butoxy. Preferred alkoxy groups are methoxy and ethoxy. As usedherein, “alkoxy-alkyl” signifies an alkyl group linked via an oxygen toanother alkyl group, which is linked to the remainder of the molecule.

As used herein, “cycloalkyl” means a ring having the number ofdesignated carbon atoms and having only single bonds between the carbonatoms. Examples of cycloalkyl include, but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Apreferred cycloalkyl group is cyclopentyl.

As used herein, “aryl” signifies a mononuclear or polynuclear aromatichydrocarbon such as phenyl, biphenyl, indene, fluorene, naphthyl(1-naphthyl, 2-naphthyl), anthracene (1-anthracenyl, 2-anthracenyl,3-anthracenyl), and phenantnthryl, depending on the number of carbonatoms designated.

Heteroaromatic ring A is A five- or six-membered heteroaromatic ringhaving the shown nitrogen atom and from 0 to 2 additional heteroatomsselected from the group consisting of oxygen, nitrogen, or sulfur andconnected by a ring carbon to the amine of the amide group shown. Ifsulphur is present, then it can be mono- or di-oxidized. If a secondnitrogen is present, then it can be N, NH, or substituted N.Heteroaromatic rings include, but are not limited to, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thiadiazolyl, oxazolyl,isoxazolyl, isothiazolyl, imidazolyl, and pyrazolyl. The ring carbonatom of the heteroaromatic ring which is connected via the amide linkageto form the compound of formula I cannot contain any substituent. Thepreferred five-membered heteroaromatic rings contain 2 or 3 heteroatomswith thiazolyl, imidazolyl, oxazolyl, and thiadiazolyl being especiallypreferred. The preferred six-membered heteroaromatic rings include, forexample, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

As used herein, “heterocycle” signifies a mono-, bi-, or tricyclic ringconsisting of carbon atoms and from one heteroatom to the maximum numberdesignated,

wherein the heteroatom is selected from oxygen, nitrogen, and sulphur.If sulphur is present, then it can be S, S(O), or S(O)₂. If nitrogen ispresent, then it can be N, NH, substituted N, or N-oxide. Theheterocycle is a non-aromatic ring, but may contain ring double bonds.If the heterocycle is monocyclic, then from 0-2 ring double bonds may bepresent. If the heterocycle is bicyclic, then from 0-4 ring double bondsmay be present. If heterocycle ring is tricyclic, then from 0-6 ringdouble bonds may be present. Preferred heterocycles include, but are notlimited to, pyrrolidine, piperidine, piperazine, homopiperazine, andmorpholine.

As used herein, “heteroaryl” signifies a mono-, bi-, or tricyclicaromatic ring consisting of carbon atoms and from one heteroatom to themaximum number designated, wherein the heteroatom is selected fromoxygen, nitrogen, and sulphur. If sulphur is present, then it can be S,S(O), or S(O)₂. If nitrogen is present, then it can be N, NH,substituted N, or N-oxide. If the heteroaryl is bicyclic, then one orboth of the rings may have a heteroatom(s) present. If the heteroaryl istricyclic, then one, two, or all three of the rings may have aheteroatom(s) present. If the heteroaryl is bicyclic, then one or bothof the two rings may be aromatic. If the heteroaryl is tricyclic, thenone, two, or all three of the two rings may be aromatic.

Examples of “heteroaryl” include, but are not limited to thiophene(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl,isoxazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, quinazolin,fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl,pyrrolyl (1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyrazolyl (1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), imidazolyl (1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl(1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl 1,2,3-triazol-5-yl,1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl), oxazolyl (2-oxazolyl,4-oxazolyl, 5-oxazolyl), isooxazolyl (isooxazo-3-yl, isooxazo-4-yl,isooxaz-5-yl), isothiazolyl (isothiazo-3-yl, isothiazo-4-yl,isothiaz-5-yl) thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl),pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl(3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl),isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl)), benzo[b]thiophenyl(benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-4-yl,benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl),2,3-dihydro-benzo[b]thiophenyl (2,3-dihydro-benzo[b]thiophen-2-yl,2,3-dihydro-benzo[b]thiophen-3-yl, 2,3-dihydro-benzo[b]thiophen-4-yl,2,3-dihydro-benzo[b]thiophen-5-yl, 2,3-dihydro-benzo[b]thiophen-6-yl,2,3-dihydro-benzo[b]thiophen-7-yl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (2-benzoxazolyl, 3-benzoxazolyl,4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl),benzothiazolyl (2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl,6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl,2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine(5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl,5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl,5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), benzo[1,3]dioxole(2-benzo[1,3]dioxole, 4-benzo[1,3]dioxole, 5-benzo[1,3]dioxole,6-benzo[1,3]dioxole, 7-benzo[1,3]dioxole), purinyl, and tetrazolyl(5-tetrazolyl, N-tetrazolyl).

As used herein, “therapeutically effective amount” is intended toinclude an amount of a compound of the present invention that iseffective when administered alone or in combination to activateglucokinase.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, e.g.,arresting or slowing its development; and/or (c) relieving thedisease-state, e.g., causing regression of the disease state itself orsome symptom of the disease state.

Utility

Glucokinase Activity Assay (I)

Glucokinase activity is assayed spectrometrically coupled to glucose6-phosphate dehydrogenase to determine compound activation ofglucokinase. The final assay contains 50 mM Hepes, pH 7.1, 50 mM KCl, 5mM MgCl₂, 2 mM dithiothreitol, 0.6 mM NADP, 1 mM ATP, 0.195 μM G-6-Pdehydrogenase (from Roche, 127 671), and 15 nM recombinant humanglucokinase. The glucokinase is human liver glucokinase N-terminallytruncated with an N-terminal His-tag ((His)-8-VEQILA Q466) and isexpressed in E. coli as a soluble protein with enzymatic activitycomparable to liver extracted GK.

The purification of His-tagged human glucokinase (hGK) was performed asfollows: The cell pellet from 50 mL E. coli culture was resuspended in 5mL extraction buffer A (25 mM HEPES, pH 8.0, 1 mM MgCl₂, 150 mM NaCl, 2mM mercaptoethanol) with the addition of 0.25 mg/mL lysozyme and 50μg/mL sodium azide. After 5 minutes at room temperature, 5 mL ofextraction buffer B (1.5 M NaCl, 100 mM CaCl₂, 100 mM MgCl₂, 0.02 mg/mLDNase 1, protease inhibitor tablet (Complete® 1697498): 1 tablet pr. 20mL buffer) was added. The extract was then centrifugated at 15.000 g for30 minutes. The resulting supernatant was loaded on a 1 mL Metal ChelateAffinity Chromatography (MCAC) Column charged with Ni²⁺. The column waswashed with 2 volumes buffer A containing 20 mM imidazole and the boundhis-tagged hGK was subsequently eluted using a 20 minute gradient of 20to 500 mM imididazol in buffer A. Fractions were examined usingSDS-gel-electrophoresis, and fractions containing hGK (MW: 52 KDa) werepooled. Finally a gelfiltration step was used for final polishing andbuffer exchange. hGK containing fractions were loaded onto a Superdex®75 (16/60) gelfiltration column and eluted with Buffer B (25 mM HEPES,pH 8.0, 1 mM MgCl₂, 150 mM NaCl, 1 mM Dithiothreitol). The purified hGKwas examined by SDS-gel electrophoresis and MALDI mass spectrometry andfinally 20% glycerol was added before freezing. The yield from 50 mL E.coli culture was generally approximately 2-3 mg hGK with a purity>90%.

The compound to be tested was added into the well in final 2.5% DMSOconcentration in an amount sufficient to give a desired concentration ofcompound, for instance 1, 5, 10, 25 or 50 μM. The reaction started afterglucose was added to a final concentration of 2, 5, 10 or 15 mM. Theassay used a 96-well UV plate and the final assay volume used was 200μl/well. The plate was incubated at 25° C. for 5 min and kinetics wasmeasured at 340 nm in SpectraMax® every 30 seconds for 5 minutes.Results for each compound were expressed as the fold activation of theglucokinase activity compared to the activation of the glucokinaseenzyme in an assay without compound after having been subtracted from a“blank”, which is without glucokinase enzyme and without compound. Thecompounds in each of the Examples exhibited activation of glucokinase inthis assay. A compound, which at a concentration of at or below 30 μMgives 1.5-fold higher glucokinase activity than the result from theassay without compound, was deemed to be an activator of glucokinase.

The glucose sensitivity of the compounds was measured at a compoundconcentration of 10 μM and at glucose concentrations of 5 and 15 mM.

Glucokinase Activity Assay (II)

Determination of glycogen deposition in isolated rat hepatocytes:

Hepatocytes were isolated from rats fed ad libitum by a two-stepperfusion technique. Cell viability, assessed by trypan blue exclusion,was consistently greater than 80%. Cells were plated ontocollagen-coated 96-well plates in basal medium (Medium 199 (5.5 mMglucose) supplemented with 0.1 μM dexamethasone, 100 units/mLpenicillin, 100 mg/mL streptomycin, 2 mM L-glutamine and 1 nM insulinwith 4% FCS at a cell density of 30,000 cells/well. The medium wasreplaced with basal medium 1 hour after initial plating in order toremove dead cells. Medium was changed after 24 hours to basal mediumsupplemented with 9.5 mM glucose and 10 nM insulin to induce glycogensynthesis, and experiments were performed the next day. The hepatocyteswere washed twice with prewarmed (37° C.) buffer A (117.6 mM NaCl, 5.4mM KCl, 0.82 mM Mg₂SO₄, 1.5 mM KH₂PO₄, 20 mM HEPES, 9 mM NaHCO₃, 0.1%w/v HSA, and 2.25 mM CaCl₂, pH 7.4 at 37° C.) and incubated in 100 μLbuffer A containing 15 mM glucose and increasing concentrations of thetest compound, such as for instance 1, 5, 10, 25, 50 or 100 μM, for 180minutes. Glycogen content was measured using standard procedures (Agius,L. et al, Biochem J. 266, 91-102 (1990)). A compound, which when used inthis assay gives a significant increase in glycogen content compared tothe result from the assay without compound, was deemed to have activityin this assay.

Glucokinase Activity Assay (III)

Stimulation of insulin secretion by glucokinase activators in INS-1 Ecells

The glucose responsive β-cell line INS-1E was cultivated as described byAsfari M et al., Endocrinology, 130, 167-178 (1992). The cells were thenseeded into 96 well cell culture plates and grown to a density ofapproximately 5×10⁴ per well. Stimulation of glucose dependent insulinsecretion was tested by incubation for 2 hours in Krebs Ringer Hepesbuffer at glucose concentrations from 2.5 to 15 mM with or withoutaddition of glucokinase activating compounds in concentrations of forinstance 1, 5, 10, 25, 50 or 100 μM, and the supernatants were collectedfor measurements of insulin concentrations by ELISA (n=4). A compound,which when used in this assay gives a significant increase in insulinsecretion in response to glucose compared to the result from the assaywithout compound, was deemed to have activity in this assay.

Synthesis

The present invention also provides a method for the synthesis ofcompounds useful as intermediates in the preparation of compounds offormula (I) along with methods for the preparation of compounds offormula (I). The compounds can be prepared readily according to theexamples. The compounds of the present invention can also be prepared bymethods known to those of skill in the art. For example, US2004/0014968,the contents of which are incorporated herein by reference, providesuseful synthetic methods.

This invention will be better understood from the following examples,which are for purposes of illustration and are not intended to limit theinvention defined in the claims which follow thereafter.

EXAMPLES

The following instrumentation is used:

-   -   Agilent series 1100 G1312A Bin Pump    -   Agilent series 1100 Column compartment    -   Agilent series 1100 G1315A DAD diode array detector    -   Agilent series 1100 MSD    -   Sedere 75 Evaporative Light Scattering detector    -   The instrument is controlled by HP Chemstation software.    -   The HPLC pump is connected to two eluent reservoirs containing:

A: 0.05% TFA in water B: 0.05% TFA in acetonitrile

The analysis is performed at 40° C. by injecting an appropriate volumeof the sample (preferably 1 μl) onto the column which is eluted with agradient of acetonitrile.

The HPLC conditions, detector settings and mass spectrometer settingsused are given in the following table.

Column Waters Xterra MS C-18 × 3 mm id 5 μm Gradient 5%-100%acetonitrile linear during 7.5 min at 1.5 mL/min Detection 210 nm(analogue output from DAD) ELS (analogue output from ELS) MS ionisationmode API-ES Scan 100-1000 amu step 0.1 amu

List of Abbreviations

-   -   TFA—Trifluoroacetic acid    -   DIPEA—Diisopropylethylamin    -   DIC—1,3-Diisopropyl carbodiimide    -   DCC—1,3-Dicyclohexyl carbodiimide    -   HOBt—N-Hydroxybenzotriazole    -   DCM—Dichloromethane    -   DMF—N,N-Dimethylformamide    -   TEA—Triethylamine    -   THF—Tetrahydrofuran

Example 1{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-aceticacid ethyl ester (Compound 1)

Iodomethylcyclopentane: Methanesulfonyl chloride (13.8 mL, 178 mmol) wasadded drop wise and at 0° C. to a solution of cyclopentanemethanol (16.2g, 162 mmol) in anhydrous pyridine (35 mL). The mixture was stirred at0° C. for 5 h, poured into water (200 mL), and extracted with methylenechloride (3×50 mL). The combined organic layers were washed with 1 M HCl(3×20 mL) and brine (2×20 mL), dried with anhydrous magnesium sulphate,and evaporated in vacuo. The residue was dissolved in anhydrous acetone(20 mL), and a solution of sodium iodide (24 g, 162 mmol) in acetone (50mL) was added. The mixture was refluxed for 5 h. The formed precipitatewas filtered off, and the filtrate was evaporated in vacuo. The residuewas distilled and the fraction boiling at 71-75° C. (110 Torr) wascollected to give iodomethylcyclopentane. Yield: 13.8 g (41%). ¹H-NMR(CDCl₃, δ ppm): 3.21 (d, J=6.9 Hz, 2H); 2.18 (hept, J=7.5 Hz, 1H);1.95-1.45 (m, 6H); 1.35-1.11 (m, 2H).

Methyl 4-(methanesulfonyl)phenyl acetate: A solution of4-(methanesulfonyl)phenyl acetic acid (21.8 g, 101 mmol), methanol (250mL), and concentrated sulfuric acid (1 mL) was heated under reflux for16 h. The reaction mixture was allowed to cool to 25° C. and evaporatedto dryness in vacuo. The residue was taken up in 10% aqueous sodiumbicarbonate (200 mL) and ethyl acetate (200 mL). The isolated waterphase was extracted with further ethyl acetate (2×200 mL), and thecombined organic phases were washed with water (100 mL), dried withanhydrous sodium sulphate, and evaporated to dryness in vacuo to givemethyl 4-(methanesulfonyl)phenyl acetate. Yield: 24.0 g (100%). ¹H-NMR(CDCl₃, δ ppm): 7.91 (d, 2H); 7.50 (d, 2H); 3.74 (s, 2H); 3.73 (s, 3H);3.05 (s, 3H).

Methyl 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionate:Diisopropylamine (8.9 mL, 63 mmol) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) in drytetrahydrofuran (60 mL) were cooled to −78° C. A 1.6 M solution ofbutyllithium in hexane (39 mL, 63 mmol) was added slowly, and themixture was stirred at −78° C. for 0.5 h. A solution of methyl4-(methanesulfonyl)phenyl acetate (13.69 g, 60 mmol) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) in drytetrahydrofuran (60 mL) was added slowly. The reaction mixture wasstirred at −78° C. for 0.5 h, and a solution of iodomethylcyclopentane(13.8 g, 66 mmol) in tetrahydrofuran (10 mL) was added slowly. Themixture was then stirred at −78° C. for 0.5 h and then allowed to warmto ambient temperature where it stayed overnight. The reaction mixturewas quenched with water (30 mL) and subsequently concentrated in vacuoto remove tetrahydrofuran. The residue was diluted with ethyl acetate(500 mL), washed with brine (2×100 mL), dried with anhydrous sodiumsulphate, and concentrated in vacuo. Column chromatography of theresidue (Silica gel, hexane/ethyl acetate (75:25)) afforded methyl3-cyclopentyl-2-(4-methanesulfonylphenyl)propionate as an oil. Yield:12.24 g (65%). ¹H-NMR (CDCl₃, δ ppm): 7.90 (d, J=8.2 Hz, 2H); 7.53 (d,J=8.2 Hz, 2H); 3.72 (t, J=7.8 Hz, 1H); 3.67 (s, 3H); 3.07 (s, 3H);2.21-2.05 (m, 1H); 1.95-1.70 (m, 8H); 0.95-1.25 (m, 2H).

3-Cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid: A mixture ofmethyl 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid (2.8 g,9.0 mmol), 1 N sodium hydroxide (19 mL), and methanol (25 mL) wasstirred at room temperature for 24 h. The reaction mixture wasconcentrated in vacuo to remove the methanol and 2 N HCl (9 mL) wasslowly added at 0° C. to give white crystals of3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid. Yield: 2.3 g(87%). mp: 160-161° C. ¹H-NMR (CDCl₃, 6 ppm): 7.90 (d, J=8.2 Hz, 2H);7.54 (d, J=8.2 Hz, 2 H); 3.72 (t, J=7.8 Hz, 1H); 3.05 (s, 3H); 2.15-2.08(m, 1H); 1.9-1.45 (m, 8H); 1.05-1.20 (m, 2H).

To a solution of 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid(200 mg, 0.67 mmol) in a mixture of dry methylene chloride (5 mL) anddry DMF (1 mL) were added HOBT (20 mg) and DCC (155 mg, 0.75 mmol), andthe mixture was stirred at room temperature for 2 h. A solution of(2-amino-5-methylthiazol-4-yl)-acetic acid ethyl ester (220 mg, 0.78mmol) and DIPEA (135 μl, 102 mg, 0.79 mmol) in dry DMF (1 mL) was addedto the reaction mixture and stirring was continued for 18 h at roomtemperature. The mixture was evaporated in vacuo and the residuepurified on a silica gel column (heptan:ethyl acetate (7:3)) to give{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-aceticacid ethyl ester. Yield: 120 mg (37%). ¹H-NMR (CDCl₃): δ 8.86 (broad s,1H), 7.91 (d, 2H), 7.52 (d, 2H), 4.14 (q, 2H), 3.66 (t, 1H), 3.57 (s,2H), 3.07 (s, 3H), 2.32 (s, 3H), 2.25-2.18 (m, 1H), 1.93-1.86 (m, 1H),1.81-1.43 (m, 7H), 1.24 (t, 3H), 1.16-1.06 (m, 2H); HPLC-MS: m/z=480(M+1); Rt=4.09 min.

Example 23-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-propionamide(Compound 2)

N-[5-(4-Methylpiperazine-1-sulfonyl)-thiazol-2-yl]-acetamide: To asolution of 2-acetamido-4-methyl-5-thiazolesulfonyl chloride (3 g, 11.8mmol) in DCM (50 mL) and TEA (3.2 mL, 23.6 mmol) was slowly addedN-methylpiperazine (1.2 g, 12.4 mmol). The reaction mixture was stirredat room temperature for 2 hours. Water (50 mL) was added, and theorganic phase was isolated. The water phase was extracted with DCM (3×75mL). The combined organic phase was dried with anhydrous magnesiumsulphate, filtered, and evaporated in vacuo to give 2.6 g of yellow,impure crystals. Purification on a silica gel column (Eluent: DCM:MeOH(9:1)) gave N-[5-(4-methylpiperazine-1-sulfonyl)thiazol-2-yl]-acetamideas light yellow crystals ofN-[5-(4-methylpiperazine-1-sulfonyl)thiazol-2-yl]-acetamide. Yield: 1.52g (41%). ¹H-NMR (CDCl₃): δ 3.20 (m, 4H); 2.55 (m, 7H); 2.32 (s, 3H);2.29 (s, 3H).

4-Methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine: Asolution of N-[5-(4-methylpiperazine-1-sulfonyl)thiazol-2-yl]-acetamide(1 g, 3.1 mmol) in methanol (5 mL) and 6 N hydrochloric acid (5 mL) washeated in a microwave oven (4×5 min at 80° C.). The reaction mixture waspartly evaporated to remove most of the methanol, and the residue waswashed with DCM (10 mL). The water phase was isolated, and the pHadjusted to 8-9. Extraction with DCM (3×25 mL), drying over anhydrousmagnesium sulphate, and evaporation in vacuo gave white crystals of4-methyl-5-(4-methyl-piperazine-1-sulfonyl)thiazol-2-ylamine. Yield:0.53 g (61%). ¹H-NMR (CDCl₃): δ 5.46 (m, 2H); 3.18 (m, 4H); 2.51 (m,4H); 2.45 (s, 3H); 2.31 (s, 3H).

3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-propionamidewas prepared from 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionicacid and 4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamineas described in Example 1. ¹H-NMR (CDCl₃): δ 13.03 (broad s, 1H), 7.91(d, 2H), 7.64 (d, 2H), 4.05 (t, 1H), 3.20 (s, 3H), 2.99 (m, 4H), 2.47(s, 3H), 2.39 (m, 4H), 2.16 (m, 4H), 1.84-1.77 (m, 1H), 1.75-1.39 (m,7H), 1.19-1.07 (m, 2H); HPLC-MS: m/z=555 (M+1); Rt=3.08 min.

Example 33-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(4-methyl-piperazin-1-yl)-thiazol-2-yl]-propionamide(Compound 3)

2-Amino-5-(4-methylpiperazin-1-yl)-thiazole: To a solution of2-amino-5-bromthiazol, HBr (500 mg, 1.9 mmol) in DMF (6 mL) were addedpotassium carbonate, anhydrous (1.0 g, 7.3 mmol) and N-methylpiperazine(215 μL, 1.9 mmol). The reaction mixture was stirred at room temperaturefor 2 hours and then filtered and evaporated to dryness in vacuo.Stirring of the residue with ethyl acetate (3 mL) gave beige crystals of2-amino-5-(4-methylpiperazin-1-yl)-thiazole.

Yield: 290 mg (76%). ¹H-NMR (CD₃OD): δ 6.34 (s, 1H), 2.94 (t, 4H), 2.56(t, 4H), 2.32 (s, 3H).

3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(4-methyl-piperazin-1-yl)-thiazol-2-yl]-propionamidewas prepared from 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionicacid and 2-amino-5-(4-methylpiperazin-1-yl)thiazole as described inExample 1. ¹H-NMR (CD₃OD): δ 7.92 (d, 2H), 7.68 (d, 2H), 6.80 (s, 1H),3.95 (t, 1H), 3.57 (m, 4H), 3.29 (m, 2H), 3.16 (m, 2H), 3.11 (s, 3H),2.95 (s, 3H), 2.22-2.15 (m, 1H), 1.88-1.43 (m, 8H), 1.21-1.11 (m, 2H);HPLC-MS: m/z=477 (M+1).

Example 4{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester (Compound 4)

(2-Aminothiazol-5-ylsulfanyl)-acetic acid ethyl ester: A mixture of2-amino-5-bromothiazole, HBr (7.26 g, 27.9 mmol), ethyl thioglycolate(10 g, 83.8 mmol), and potassium carbonate (7.7 g, 55.9 mmol) in DMF (25mL) was stirred at room temperature for 2 hours. The reaction mixturewas filtered and water (150 mL) and ethyl acetate (400 mL) were added.The organic phase was isolated and washed with brine (3×50 mL), driedover anhydrous magnesium sulphate, and evaporated to dryness in vacuo togive (2-aminothiazol-5-ylsulfanyl)-acetic acid ethyl ester. Yield: 3.3 g(54%). ¹H-NMR (DMSO-d₆): δ 7.6 (s, 2H), 7.00 (s, 1H), 4.08 (q, 2H), 3.45(s, 2H), 1.17 (t, 3H).

{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester was prepared from3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid and(2-aminothiazol-5-ylsulfanyl)-acetic acid ethyl ester as described inExample 1. ¹H-NMR (CDCl₃): δ 11.78 (broad s, 1H), 7.88 (d, 2H), 7.57 (d,2H), 7.54 (s, 1H), 4.18 (q, 2H), 3.80 (t, 1H), 3.46 (s, 2H), 3.05 (s,3H), 2.31-2.23 (m, 1H), 1.92-1.85 (m, 1H), 1.80-1.40 (m, 7H), 1.26 (t,3H), 1.12 (m, 2H); HPLC-MS: m/z=497 (M+1).

Example 5{5-Chloro-2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester (Compound 5)

(2-Amino-5-chloro-thiazol-4-yl)-acetic acid ethyl ester: To a solutionof (2-aminothiazol-4-yl)-acetic acid ethyl ester (2.2 g, 11.8 mmol) inacetic acid (200 mL) was added N-chlorosuccinimide (1.73 g, 13.0 mmol),and the mixture was stirred at room temperature for 3 hours. The solventwas removed in vacuo, and the residue was stirred with acetone to givecrystals of 2-amino-5-chloro-thiazol-4-yl)-acetic acid ethyl ester, HCl.Yield: 1.45 g (48%). ¹H-NMR (DMSO-d₆): δ 4.08 (q, 2H), 3.60 (s, 2H),1.17 (t, 3H).

{5-Chloro-2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-4-yl}-aceticacid ethyl ester was prepared from3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid and2-amino-5-chloro-thiazol-4-yl)-acetic acid ethyl ester as described inExample 1. ¹H-NMR (CDCl₃): δ 9.28 (broad s, 1H), 7.91 (d, 2H), 7.53 (d,2H), 4.15 (q, 2H), 3.72 (t, 1H), 3.65 (s, 2H), 3.08 (s, 3H), 2.24-2.17(m, 1H), 2.01-1.46 (m, 8H), 1.25 (t, 3H), 1.16-1.06 (m, 2H); HPLC-MS:m/z=499 (M+1).

Example 6{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-aceticacid (Compound 6)

{2-[3-Cyclopentyl-2-(4-methanesulfonylphenyl)-propionylamino]-5-methyl-thiazol-4-yl}-aceticacid ethyl ester (49 mg, 0.1 mmol), dioxan (0.5 mL), and 1 N sodiumhydroxide were stirred at room temperature for 20 h. The pH was adjustedto approx. 3 with 1 N hydrochloric acid (0.5 mL), the reaction mixturewas concentrated in vacuo, and the precipitate was isolated byfiltration. Yellow crystals of the title compound were washed with waterand dried to give 43 mg (yield: 93%). ¹H-NMR (CDCl₃): δ 7.85 (d, 2H),7.58 (d, 2H), 3.78 (t, 1H), 3.62 (s, 2H), 3.01 (s, 3H), 2.42 (s, 3H),2.22-2.15 (m, 1H), 1.93-1.86 (m, 1H), 1.75-1.49 (m, 7H), 1.15-1.02 (m,2H); HPLC-MS: m/z=451 (M+1).

Example 7{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-aceticacid (Compound 7)

The title compound was prepared as described in Example 6. ¹H-NMR(CDCl₃): δ 7.90 (d, 2H), 7.62 (d, 2H), 7.38 (s, 1H), 3.82 (t, 1H), 3.47(s, 2H), 3.05 (s, 3H), 2.26-2.19 (m, 1H), 1.96-1.89 (m, 1H), 1.80-1.42(m, 7H), 1.20-1.07 (m, 2H); HPLC-MS: m/z=469 (M+1).

Example 8{5-Chloro-2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid (Compound 8)

The title compound was prepared as described in example 6. ¹H-NMRCDCl₃): δ 7.87 (d, 2H), 7.58 (d, 2H), 3.77 (t, 1H), 3.69 (s, 2H), 3.03(s, 3H), 2.21-2.14 (m, 1H), 1.95-1.88 (m, 1H), 1.77-1.41 (m, 7H),1.16-1.03 (m, 2H); HPLC-MS: m/z=471/473 (3:1; M+1).

Example 9(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)-propionamide(Compound 9)

(4S,2′R)-4-benzyl-3-[3-cyclopentyl-2-(4-methanesulfonyl phenyl)propionyl]oxazolidin-2-one: A solution of(S)-(−)-4-benzyl-2-oxazolidinone (8.70 g, 49 mmol) in dry THF (70 mL)was cooled to −78° C. and then treated with a 1.6 M solution ofbutyllithium in hexanes (29 mL, 47 mmol). The solution was stirred at−78° C. for 0.5 h and then allowed to warm to 25° C. where it wasstirred for 1 h. Parallel to it; a solution of racemic3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid (11.63 g, 39mmol) in dry THF (83 mL) was cooled to 0° C. and TEA (6.7 mL, 47 mmol)was added. Trimethylacetyl chloride (5.9 g, 49 mmol) was added drop wiseand the reaction mixture was stirred at 0° C. for 2 h and then cooled to−78° C. The mixture containing the oxazolidinone was then added to thecold mixed anhydride solution. The resulting mixture was stirred at −78°C. for 1 h and then stirred at ambient temperature overnight. Theresulting mixture was quenched with water (250 mL) and then concentratedin vacuo to remove TFH. The aqueous residue was extracted with ethylacetate (3×250 mL). The combined organic layers were washed with brine(3×100 mL), dried with anhydrous sodium sulphate and evaporated invacuo. The diastereoisomers were separated by flash columnchromatography (silica gel, hexane/ethyl acetate 75:25) affording thehigher moving product,(4S,2′R)-4-benzyl-3-[3-cyclopentyl-2-(4-methanesulfonyl phenyl)propionyl]oxazolidin-2-one. Yield 6.2 g (34%). ¹H NMR (CDCl₃): δ 7.92(d, J=8.3 Hz, 2H); 7.66 (d, J=8.3 Hz, 2 H); 7.24-7.18 (m, 3H); 7.02-6.93(m, 2H); 5.17 (t, J=7.5 Hz, 1H); 4.80-4.65 (m, 1 H); 4.30-4.05 (m, 2H);3.22-3.05 (m, 1H); 3.08 (s, 3H); 2.58 (dd, J=9.4 and 13.6 Hz, 1H);2.22-2.02 (m, 1H); 1.95-1.35 (m, 8H); 1.30-1.00 (m, 2H).

(2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid: An aqueoussolution of lithium hydroperoxide was prepared by mixing a solution oflithium hydroxide monohydrate (1.4 g, 33 mmol) in water (7 mL) and 30%aqueous hydrogen peroxide (6.8 mL, 66 mmol). The solution was cooled to0° C. and then slowly added to a solution of(4S,2′R)-4-benzyl-3-[3-cyclopentyl-2-(4-methanesulfonylphenyl)propionyl]oxazolidin-2-one (7.15 g, 15.7 mmol) in THF (45 mL) andwater (15 mL). The reaction mixture was stirred at 0° C. for 1.5 h,quenched with saturated aqueous sodium sulphite solution (20 mL) anddiluted with water (300 mL). The aqueous layer was washed with diethylether (4×200 mL), acidified with HCl to pH=2, and extracted with ethylacetate (3×200 mL). The ethyl acetate phases were dried with anhydroussodium sulphate and evaporated to dryness in vacuo to give(2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid. Yield:4.59 g (98%). mp: 132-141° C. ¹H-NMR (CDCl₃): δ 7.90 (d, 2H); 7.54 (d,2H); 3.72 (t, 1H); 3.06 (s, 3H); 2.20-2.03 (m, 1H); 1.95-1.40 (m, 8H);1.30-1.00 (m, 2H). [α]²³=−50.0° (c=0.02 g/100 mL, chloroform).

The title compound was prepared from(2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid and2-amino-5-thiocyanothiazole as described in Example 1. ¹H-NMR (CDCl₃): δ7.92 (d, 2H), 7.71 (s, 1H), 7.55 (d, 2H), 3.77 (t, 1H), 3.07 (s, 3H),2.29-2.21 (m, 1H), 1.98-1.89 (m, 1H), 1.82-1.69 (m, 2H), 1.67-1.57 (m,3H), 1.53-1.47 (m, 2H), 1.19-1.08 (m, 2H); HPLC-MS: m/z=436 (M+1).

Example 10(R)-3-Cyclopentyl-N-[5-(2-diethylamino-ethylsulfanyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phenyl)-propionamide(Compound 10)

To a solution of(R)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)-propionamide(200 mg, 0.46 mmol) in methanol (2.5 mL) and DCM (2.5 mL) was addeddithiothreitol (71 mg, 0.46 mmol), and the mixture was stirred at roomtemperature for 1 h. 2-Chloroethyl-diethylamine (158 mg, 0.92 mmol),potassium carbonate (235 mg, 0.46 mmol), and potassium iodide (10 mg)were added and the reaction mixture was stirred for another 3 h at roomtemperature. Water (5 mL) and DCM (10 mL) were added and the organicphase was isolated and dried over anhydrous magnesium sulphate. Thesolvent was removed in vacuo, and the residue was purified on a silicagel column (isocratic from 100% DMC to 100% ethyl acetate with 1% TEA)to give colourless crystals of(R)-3-cyclopentyl-N-[5-(2-diethylamino-ethylsulfanyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phenyl)-propionamide.Yield: 150 mg (64%). ¹H-NMR (CDCl₃): δ 11.50 (broad s, 1H), 7.86 (d,2H), 7.51 (d, 2H), 7.48 (s, 1H), 3.76 (t, 1H), 3.04 (s, 3H), 2.86 (t,2H), 2.71 (t, 2H), 2.54 (q, 4H), 2.26 (m, 1H), 1.90 (m, 1H), 1.79-1.43(m, 8H), 1.12 (m, 1H), 1.00 (t, 6H); HPLC-MS: m/z=510 (M+1).

Example 11(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methylsulfanyl-thiazol-2-yl)-propionamide(Compound 11)

The title compound was prepared from(R)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)-propionamideand methyl iodide as described in Example 10. ¹H-NMR (CDCl₃): δ 11.8(broad s, 1H), 7.86 (d, 2H), 7.52 (d, 2H), 7.44 (s, 1H), 3.79 (t, 1H),3.04 (s, 3H), 2.46 (s, 3H), 2.27 (m, 1H), 1.89 (m, 1H), 1.81-1.44 (m,7H), 1.12 (m, 2H); HPLC-MS: m/z: 425 (M+1).

Example 123-Cyclopentyl-N-(5-diethylcarbamoylmethylsulfanyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide(Compound 12)

To a solution of{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-aceticacid (33 mg, 70.4 mmol) in DMF (0.5 mL) was added3-hydroxy-1,2,3-benzotriazin-4-(3H)-one (12 mg, 73.5 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14 mg, 73mmol). The reaction mixture was stirred at room temperature for 2 hoursafter which diethyl amine (10 μL, 96.3 mmol) and DIPEA (12 μL, 70.3mmol) were added. Stirring was continued for 20 hours. The reactionmixture was purified by HPLC(C18, gradient 25%-100% acetonitrile) togive3-cyclopentyl-N-(5-diethylcarbamoylmethylsulfanyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamideas an oil. Yield: 15 mg (42%). ¹H-NMR (CDCl₃): δ 7.91 (d, 2H), 7.62 (d,2H), 7.45 (s, 1H), 3.93 (t, 1H), 3.63 (s, 3H), 3.38 (q, 2H), 3.31 (q,2H), 3.05 (s, 3H), 2.28-2.21 (m, 1H), 1.97-1.90 (m, 1H), 1.75-1.47 (m,7H), 1.23-1.11 (m, 8H); HPLC-MS: m/z: 525 (M+1).

Example 13{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-sulfonyl}-aceticacid (Compound 13)

To a mixture of montmorillonite KSF (150 mg), water (50 μL), DCM (0.5mL), and oxone (105 mg) was added a solution of{2-[3-cyclopentyl-2-(4-methanesulfonylphenyl)-propionylamino]-thiazol-5-ylsulfanyl}-aceticacid (32 mg, 68.3 mmol) in DCM (0.7 mL). The reaction mixture wasstirred at room temperature for 18 hours, filtered and evaporated todryness in vacuo to give the title compound as white crystals. Yield: 9mg (25%). ¹H-NMR (CDCl₃): δ 7.83 (m, 3H), 7.51 (d, 2H), 4.21 (s, 2H),3.81 (t, 1H), 3.00 (s, 3H), 2.14 (m, 1H), 1.88 (m, 1H), 1.69-1.38 (m,8H), 1.06 (m, 2H); HPLC-MS: m/z: 501 (M+1).

Example 14(R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester (Compound 14)

The title compound was prepared from(R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid and(2-amino-thiazol-4-yl)-acetic acid ethyl ester as described inExample 1. ¹H-NMR (CDCl₃): δ 11.07 (broad s, 1H), 7.89 (d, 1H), 7.54 (m,3H), 4.18 (q, 2H), 3.76 (t, 1H), 3.45 (s, 2H), 3.05 (s, 3H), 2.27 (m,1H), 1.90 (m, 1H), 1.81-1.44 (m, 8H), 1.26 (t, 3H), 1.12 (m, 2H);HPLC-MS: m/z: 498 (M+1).

Example 15(R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]thiazol-5-ylsulfanyl}-aceticacid (Compound 15)

The title compound was prepared from(R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester as described in Example 6. ¹H-NMR (CDCl₃): δ 7.90 (d,2H), 7.62 (d, 2H), 7.34 (s, 1H), 3.83 (t, 1H), 3.44 (s, 2H), 3.04 (s,3H), 2.29-2.17 (m, 1H), 1.98-1.90 (m, 1H), 1.80-1.46 (m, 7H), 1.20-1.08(m, 2H); HPLC-MS: m/z: 469 (M+1).

Example 16(R)-3-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester (Compound 16)

3-(2-Amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester: To asolution of 2-amino-5-bromothiazole (50 g, 192 mmol) in DMF (300 mL)were added potassium carbonate (53 g, 384 mmol) and ethyl3-mercaptopropionate (25.8 g, 192 mmol). The reaction mixture wasstirred at room temperature for 36 h. The mixture was partitionedbetween water (500 mL) and ethyl acetate (500 mL) and the isolated waterphase was extracted with ethyl acetate (250 mL). The combine organicphases were washed with water (250 mL) and 10% aqueous sodiumhydrogencarbonate (250 mL), dried over anhydrous magnesium sulphate andevaporated to dryness in vacuo to give3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. Yield: 19.6g (44%). ¹H-NMR (CDCl₃): δ 7.07 (s, 1H); 4.15 (q, 2H); 2.88 (t, 2H);2.61 (t, 2H); 1.26 (t, 3H); HPLC-MS: m/z: 233 (M+1).

(R)-3-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester was prepared from(R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid and3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester as describedin Example 1. ¹H_NMR (CD₃OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.40 (s,1H), 4.08 (q, 2H), 3.96 (t, 1H), 3.09 (s, 3H), 2.92 (t, 2H), 2.57 (t,2H), 2.21 (m, 1H), 1.88-1.48 (m, 8H), 1.22-1.17 (m, 5H); HPLC-MS: m/z:511 (M+1).

Example 17(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-oxo-2-piperazin-1-yl-ethylsulfanyl)-thiazol-2-yl]-propionamide(Compound 17)

(R)-4-(2-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-acetyl)-piperazine-1-carboxylicacid tert-butyl ester was prepared from(R)-{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-aceticacid and tert-butyl-1-piperazinecarboxylate as described in Example 12.¹H-NMR (CDCl₃): δ 7.87 (d, 2H), 7.54 (d, 2H), 7.44 (s, 1H), 3.87 (t,1H), 3.66 (s, 2H), 3.61-3.46 (m, 8H), 3.05 (s, 3H), 2.24 (m, 1H), 1.89(m, 1H), 1.79-1.54 (m, 5H), 1.48 (m, 11H), 1.14 (m, 2H); HPLC-MS: m/z:637 (M+1), 582 (M+1-C(CH₃)₃)

(R)-4-(2-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-acetyl)-piperazine-1-carboxylicacid tert-butyl ester (50 mg, 78.6 mml) was dissolved in a mixture ofchloroform (2 mL) and TFA (1 mL). The mixture was stirred at roomtemperature for 2 h and evaporated to dryness in vacuo to give whitecrystals of(R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-[5-(2-oxo-2-piperazin-1-yl-ethylsulfanyl)-thiazol-2-yl]-propionamide.¹H-NMR (CD₃OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.48 (s, 1H), 3.97 (t,1H), 3.81 (m, 4H), 3.73 (s, 3H), 3.29-3.23 (m, 4H), 3.10 (s, 3H),2.24-2.16 (m, 1H), 1.90-1.75 (m, 3H), 1.69-1.59 (m, 3H), 1.50 (m, 2H),1.17 (m, 2H); HPLC-MS: m/z: 537 (M+1).

Example 18(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-morpholin-4-yl-2-oxo-ethylsulfanyl)-thiazol-2-yl]-propionamide(Compound 18)

The title compound was prepared from(R)-{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-aceticacid and morpholine as described in Example 12. ¹H-NMR (CD₃OD): δ 7.92(d, 2H), 7.67 (d, 2H), 7.48 (s, 1H), 3.96 (t, 1H), 3.64 (s, 2H),3.63-3.46 (m, 8H), 3.09 (s, 3H), 2.25-2.18 (m, 1H), 1.88-1.75 (m, 3H),1.64 (m, 3H), 1.50 (m, 2H), 1.17 (m, 2H); HPLC-MS: m/z: 538 (M+1).

Example 19(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-{5-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethylsulfanyl]-thiazol-2-yl}-propionamide(Compound 19)

The title compound was prepared from(R)-{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-aceticacid and 1-methylpiperazine as described in Example 12. ¹H-NMR (CD₃OD):δ 7.92 (d, 2H), 7.67 (d, 2H), 7.50 (s, 1H), 4.83-4.15 (broad m, 2H),3.96 (t, 1H), 3.72 (s, 2H), 3.60-3.45 (broad m, 3H), 3.12-3.00 (broad m,3H), 3.10 (s, 3H), 2.92 (s, 3H), 2.25-2.17 m, 1H), 1.90-1.75 (m, 3H),1.70-1.60 (m, 3H), 1.51 (m, 2H), 1.18 (m, 2H); HPLC-MS: m/z: 551 (M+1).

Example 20(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-oxo-2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-propionamide(Compound 20)

The title compound was prepared from(R)-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-aceticacid and piperidine as described in Example 12. ¹H-NMR (CD₃OD): δ 7.92(d, 2H), 7.66 (d, 2H), 7.46 (s, 1H), 3.96 (t, 1H), 3.63 (s, 2H), 3.48(broad t, 2H), 3.43 (broad t, 2H), 3.09 (s, 3H), 2.25-2.18 (m, 1H),1.88-1.48 (m, 14H), 1.17 (m, 2H); HPLC-MS: m/z: 536 (M+1).

Example 21(R)-3-Cyclopentyl-N-[5-(2-dimethylamino-ethylsulfanyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phenyl)-propionamide(Compound 21)

The title compound was prepared from(R)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)-propionamideand 2-(dimethylamino)ethyl chloride as described in Example 10. ¹H-NMR(CD₃OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.55 (s, 1H), 3.96 (t, 1H), 3.29(m, 2H), 3.10 (s, 3H), 3.06 (m, 2H), 2.87 (s, 6H), 2.26-2.19 (m, 1H),1.89-1.48 (m, 8H), 1.18 (m, 2H); HPLC-MS: m/z: 482 (M+1).

Example 22(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-morpholin-4-yl-ethylsulfanyl)-thiazol-2-yl]-propionamide(Compound 22)

The title compound was prepared from(R)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)-propionamideand 4-(2-chloroethyl)morpholine as described in Example 10. ¹H-NMR(CD₃OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.55 (1H), 3.96 (t, 1H),4.00-3.37 (broad m, 8H), 3.34 (m, 2H), 3.10 (s, 3H), 3.09-3.05 (m, 2H),2.26-2.29 (m, 1H), 1.89-1.47 (m, 8H), 1.18 (m, 2H); HPLC-MS: m/z: 524(M+1).

Example 23(R)-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-propionamide(Compound 23)

The title compound was prepared from(R)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)-propionamideand 4-(2-chloroethyl)piperidine as described in Example 10. ¹H-NMR(CD₃OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.54 (s, 1H), 3.96 (t, 1H), 3.48(broad d, 2H), 3.28-3.03 (m, 2H), 3.10 (s, 3H), 3.07-3.03 (m, 2H), 2.91(broad t, 2H), 2.26-2.29 (m, 1H), 1.92-1.45 (m, 14H), 1.18 (m, 2H);HPLC-MS: m/z: 522 (M+1).

Example 24(R)-3-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-propionicacid (Compound 24)

The title compound was prepared from(R)-3-{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester as described in Example 6. ¹H-NMR (CD₃OD): δ 7.92 (d,2H), 7.67 (d, 2H), 7.42 (s, 1H), 3.97 (t, 1H), 3.10 (s, 3H), 2.92 (t,2H), 2.56 (t, 2H), 2.25-2.18 (m, 1H), 1.90-1.48 (m, 8H), 1.17 (m, 2H);HPLC-MS: m/z: 483 (M+1).

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications. and substitutions can bemade therein without departing from the spirit and scope of the presentinvention. For example, effective dosages other than the preferreddosages as set forth herein may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forglucokinase-deficiency mediated disease(s). Likewise, the specificpharmacological responses observed may vary according to and dependingon the particular active compound selected or whether there are presentpharmaceutical carriers, as well as the type of formulation and mode ofadministration employed, and such expected variations or differences inthe results are contemplated in accordance with the objects andpractices of the present invention.

1.-24. (canceled)
 25. A compound of formula I:

wherein, the * indicates an asymmetric atom; R¹ is selected from thegroup consisting of H, Cl, F, Br, I, NH₂, —NHOH, —CN, —NO₂, C₁₋₆ alkyl,—OR⁵, —C(O)OR⁶, perfluoro-C₁₋₆ alkyl, C₁₋₆ alkyl-S—, perfluoro-C₁₋₆alkyl-S—, C₁₋₆ alkyl-SO₂—, perfluoro-C₁₋₆ alkyl-SO₂—, C₁₋₆ alkoxy-C₁₋₆alkyl-SO₂—, C₁₋₆ alkyl-S(O)—, and —SO₂NR¹³R¹⁴; R² is selected from thegroup consisting of C₁₋₆ alkyl-SO₂—, C₃₋₆ cycloalkyl-SO₂—,perfluoro-C₁₋₆ alkyl-SO₂—, and C₁₋₆ alkoxy-C₁₋₆ alkyl-SO₂—; R³ iscyclopentyl; ring A is a di-substituted thiazole; wherein thesubstituent is selected from: Cl; CF₃; C₁₋₄ alkyl; —(CH₂)_(n)—C(O)R⁷;—(CH₂)_(n)—C(O)OH; —(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)—C(O)NR¹⁰R¹¹; and—(CH₂)_(n)—S(O)_(p)—(CH₂)_(n)-5-6 membered heterocycle consisting ofcarbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and N, and Nis substituted with 0-1 C₁₋₄ alkyl; and, R⁷, at each occurrence, isindependently selected from C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R⁵, at eachoccurrence, is independently selected from the group consisting of H,C₁₋₆ alkyl, and perfluoro-C₁₋₆ alkyl; R⁶, at each occurrence, isindependently C₁₋₆ alkyl; R⁸, at each occurrence, is independentlyselected from the group consisting of H, C₁₋₈ alkyl, —(CH₂)_(n)—OH,—(CH₂)_(n)—C(O)OH, aryl, and 5-10 membered heteroaryl consisting ofcarbon atoms and 1-3 heteroatoms selected from S(O)_(p), O, and N; R⁹,at each occurrence, is independently selected from the group consistingof H, C₁₋₈ alkyl, —(CH₂)_(n)—OH, —(CH₂)_(n)—C(O)OH, aryl, and 5-10membered heteroaryl consisting of carbon atoms and 1-3 heteroatomsselected from S(O)_(p), O, and N; alternatively, R⁸ and R⁹, togetherwith the nitrogen to which they are attached form a 5-6 memberedheterocycle, consisting of, in addition to the nitrogen atom to which R⁸and R⁹ are attached, carbon atoms and 0-2 heteroatoms selected fromS(O)_(p), O, and N; R¹⁰, at each occurrence, is independently selectedfrom the group consisting of H; C₁₋₆ alkyl; —(CH₂)_(n)—OH;—(CH₂)_(n)—C(O)OH; —(CH₂)_(n)—C₃₋₈ cycloalkyl; —(CH₂)_(n)-aryl;—(CH₂)_(n)-5-10 membered heterocycle consisting of carbon atoms and 1-3heteroatoms selected from S(O)_(p), O, and N; —(CH₂)_(n)-5-10 memberedheteroaryl consisting of carbon atoms and 1-3 heteroatoms selected fromS(O)_(p), O, and N; —(CH₂)_(n)—NHR⁷; and —(CH₂)_(p)—NR⁷R⁷; R¹¹, at eachoccurrence, is independently selected from the group consisting of H;C₁₋₆ alkyl; —(CH₂)_(n)—OH; —(CH₂)_(n)—C(O)OH; —(CH₂)_(n)—C₃₋₈cycloalkyl; —(CH₂)_(n)-aryl; —(CH₂)_(n)-5-10 membered heterocycleconsisting of carbon atoms and 1-3 heteroatoms selected from S(O)_(p),O, and N; —(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atomsand 1-3 heteroatoms selected from S(O)_(p), O, and N; —(CH₂)_(n)—NHR⁷;and —(CH₂)_(n)—NR⁷R⁷; alternatively, R¹⁰ and R¹¹, together with thenitrogen to which they are attached form a 5-6 membered heterocycle,consisting of, in addition to the nitrogen atom to which R¹⁰ and R¹¹ areattached, carbon atoms and 0-2 heteroatoms selected from S(O)_(p), O,and N; and wherein the heterocycle thus formed is substituted with 0-2R¹²; R¹², at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, Cl, F, Br, I, NO₂, —(CH₂)_(n)—C(O)OH, NR⁸R⁹,NHS(O)₂CH₃, S(O)₂CH₃, and S(O)₂NH₂; R¹³, at each occurrence, isindependently selected from the group consisting of H and C₁₋₄ alkyl;R¹⁴, at each occurrence, is independently selected from the groupconsisting of H and C₁₋₄ alkyl; p, at each occurrence, is selected from0, 1, and 2; and n, at each occurrence, is independently selected from0, 1, 2, 3, 4, 5, and 6, or a pharmaceutically acceptable salt thereof.26. A compound of claim 25, wherein in ring A each substituent isindependently selected from the group consisting of: Cl; CH₃;—CH₂—C(O)OR⁷; —CH₂—C(O)OH; and —S(O)₂-piperazine optionally substitutedwith CH₃; and, R⁷, at each occurrence, is independently selected fromC₁₋₂ alkyl.
 27. A compound of claim 25 wherein n is
 1. 28. A compound ofclaim 25 wherein n is
 2. 29. A compound of claim 25, wherein R⁸ and R⁹,together with the nitrogen to which they are attached form a heterocycleselected from: piperazine, piperidine, homopiperazine, and morpholine.30. A compound of claim 25, wherein R¹⁰ and R¹¹, together with thenitrogen to which they are attached form a heterocycle selected from thegroup consisting of: piperidine, piperazine, homopiperazine,pyrrolidine, and morpholine.
 31. A compound of claim 25, wherein theasymmetric carbon shown is in the R configuration.
 32. A compound ofclaim 25 wherein R¹ is selected from the group consisting of H, Cl, F,Br, I, perfluoro-C₁₋₆ alkyl, NO₂, NH₂, C₁₋₆ alkyl-SO₂—, and —SO₂NR¹³R¹⁴;and, R² is C₁₋₆ alkyl-SO₂—.
 33. A compound of claim 32, wherein R¹ is H.34. A compound of claim 32, wherein R¹ is selected from the groupconsisting of Cl, CF₃, and CH₃.
 35. A compound of claim 32, wherein R¹is H and R² is CH₃—SO₂—.
 36. A compound selected from the groupconsisting of:{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-aceticacid ethyl ester,3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-propionamide,{5-Chloro-2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-4-yl}-aceticacid ethyl ester,{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-aceticacid, and{5-Chloro-2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-4-yl}-aceticacid, or a pharmaceutically acceptable salt thereof.
 37. Apharmaceutical composition comprising: a pharmaceutically acceptablecarrier and a compound of claim 25 or a pharmaceutically acceptable saltthereof.